Morphinan derivative

ABSTRACT

A morphinan derivative represented by the following general formula (I): 
     
       
         
         
             
             
         
       
     
     wherein R 1  represents hydrogen, C 1-10  alkyl, cycloalkylalkyl where the cycloalkyl moiety has 3 to 6 carbon atoms, and the alkylene moiety has 1 to 5 carbon atoms, etc.; R 2  represents heterocyclic ring containing 1 to 4 heteroatoms selected from N, O and S and at least one carbon atom as ring-constituting atoms, containing at least one set of adjacent ring-constituting atoms bound by a double bond, and further substituted with at least one oxo group; Y binds to a carbon atom as a ring-constituting atom of R 2 ; R 3 , R 4 , and R 5  represent hydrogen, hydroxy, etc.; R 6a  and R 6b  represent hydrogen, etc.; R 7  and R 8  represent hydrogen, etc.; R 9  and R 10 , which are the same or different, represent hydrogen, etc.; X represents O or CH 2 ; and Y represents C(═O)); a tautomer or stereoisomer of the compound, or a pharmaceutically acceptable salt thereof, or a solvate thereof is used as an anxiolytic drug, antidepressant, etc.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a Continuation of U.S. application Ser. No.17/069,589, filed Oct. 13, 2020, which is a Continuation of U.S.application Ser. No. 16/517,081, filed Jul. 19, 2019, now U.S. Pat. No.10,995,092, issued on May 4, 2021, which is a Continuation of U.S.application Ser. No. 15/558,026, now U.S. Pat. No. 10,442,802, issued onOct. 15, 2019, which is a National Stage of PCT/JP2016/058475, filedMar. 17, 2016, which claims priority to Japanese Application No.2015-054079, filed Mar. 17, 2015, the contents of all of which areexpressly incorporated by reference herein in their entireties.

TECHNICAL FIELD

The present invention relates to a morphinan derivative having an opioidδ receptor agonistic activity.

BACKGROUND ART

Opioids bind to opioid receptors to exhibit the effect thereof, andthere are three kinds of subtypes of the opioid receptors, i.e., μ, δ,and κ receptors. It is known that agonists of each of the threesubtypes, i.e., μ, δ, and κ, have analgesic effects.

However, although morphine, an agonist of the opioid μ receptor showinga high affinity to the receptor, has a potent analgesic effect, it alsoshows adverse effects such as dependence, drug abuse, tolerance,respiratory depression, constipation caused by suppression ofgastrointestinal motility, nausea and vomiting, blood pressurereductions, bradycardia, cough reflex inhibition, and sleepiness.

Although eptazocine, a selective agonist of the opioid κ receptor, has apotent analgesic effect, and shows mild dependence, tolerance,sleepiness, constipation, and respiratory depression, it causessweating, nausea and vomiting, and thirst.

It is also known that activation of the opioid δ receptor providesanalgesic, antidepressive, and anxiolytic effects. For example, it isknown that enkephalin, an endogenous ligand of the opioid δ receptor,has an analgesic effect. There are also known that anxiety-likebehaviors and depression-like behaviors increase in opioid δreceptor-deficient mice (Non-patent document 1), and enhancement of theenkephalin-δ receptor system is related to emotion regulation(Non-patent document 2). Further, since the antidepressive andanxiolytic-like-effects of various δ receptor agonists are endogenousligand of the opioid δ receptor, has an analgesic effect. There are alsoknown that anxiety-like behaviors and depression-like behaviors increasein opioid δ receptor-deficient mice (Non-patent document 1), andenhancement of the enkephalin-δ receptor system is related to emotionregulation (Non-patent document 2). Further, since the antidepressiveand anxiolytic-like-effects of various δ receptor agonists areantagonized by a δ receptor antagonist in various rat and mouse anxietyand depression models, usefulness of δ receptor-selective agonists asantidepressive and anxiolytic drugs have been demonstrated (Non-patentdocuments 3 to 7. Patent documents 1 and 2). It is expected that anagonist that selectively activates the opioid δ receptor does not showor scarcely shows adverse effects that are induced through activation ofthe opioid μ receptor or opioid κ receptor.

In addition, it is suggested that activation of the δ receptor showseffects for improving neurodegenerative diseases such as Parkinson'sdisease and Alzheimer's disease, ischaemia or cerebral stroke, urinarydysfunction, HIV infection, alcohol dependence, diabetes, and the like(Non-patent document 8). Various compounds have so far been reported asopioid δ agonists, and analgesic effects, antidepressive effects, andanxiolytic effects thereof have been verified (Patent documents 1 to 6,Non-patent document 9). It has also been reported that some opioid δagonists such as SNC80 and BW373U86 induce convulsion (Non-patentdocuments 5, 6, and 10).

As antidepressants, tetracyclic antidepressants and triazolopyridinetype antidepressants have been developed in addition to the classictricyclic antidepressants and monoamine oxidase inhibitors, and inrecent years, selective serotonin reuptake inhibitors (SSRI),serotonin-noradrenalin reuptake inhibitors (SNRI), and noradrenergic andspecific serotonergic antidepressants (NaSSA) are frequently used.However, effectiveness of all these antidepressants is not so high asevaluated in terms of remission rate. Usefulness thereof is alsolimitative, because of early development of increased aggression afterstart of administration, risk of suicidal ideation and suicide attemptof youth age patients, and the like.

As anxiolytic drugs, although benzodiazepine type drugs are widely used,this type of drugs have outstanding problems, for example, difficulty inuse for elderly people and patients showing a bad general state, becauseof adverse effects of them such as dependence, hypnotic action, musclerelaxation, sedation, and cognitive function decline at regular dose.Although indications of SSRI and SNRI developed as antidepressants arerecently expanded to various anxiety disorders, they do not showimmediate effects, and also show adverse effects. Although anestheticdrugs such as barbiturate also show anxiolytic effects, effective doseand fatal dose thereof are close to each other, and therefore they aredrugs having risks.

Therefore, it is desired to develop an anxiolytic and an antidepressantthat show effects thereof through a mechanism different from those ofthe presently used drugs, and show improved adverse effects and safety.

PRIOR ART REFERENCES Patent Documents

-   Patent document 1: Japanese Patent Unexamined Publication (Kohyo)    No. 2006-522775-   Patent document 2: WO2001/046192-   Patent document 3: WO2008/001859-   Patent document 4: WO2013/035833-   Patent document 5: WO2014/021273-   Patent document 6: WO2014/136305

Non-Patent Documents

-   Non-patent document 1: Nature Genetics, 2000, 25, 195-   Non-patent document 2: Neuroscience, 2006, 135, 306-   Non-patent document 3: J. Pharmacol. Exp. Ther., 2011, 338, 195-   Non-patent document 4: Trends in Neurosciences, 2013, 36, 195-   Non-patent document 5: Behavioral Brain Research, 2011, 223, 271-   Non-patent document 6: Neuropharmacology, 2013, 67, 485-   Non-patent document 7: Current Neuropharmacology, 2012, 10, 231-   Non-patent document 8: Psychopharmacology (Berl), 2013, 228, 1-   Non-patent document 9: Tetrahedron, 2011, 67, 6682-   Non-patent document 10: The International Narcotics Research    Conference 2014, Jul. 13, 2014

SUMMARY OF THE INVENTION Problem to be Solved by the Invention

An object of the present invention is to provide an anxiolytic, anantidepressant, an analgesic drug, a therapeutic agent for Parkinson'sdisease, and a therapeutic agent for pollakiuria and urinaryincontinence that are highly effective, show less adverse effects suchas dependence, tolerance, respiratory depression, constipation, nauseaand vomiting, blood pressure reductions, bradycardia, cough reflexinhibition, hypnotic effects, muscle relaxation, sedation, cognitivefunction decline, sweating, and thirst, and are safe. Another object ofthe present invention is to provide a safe medicament that can evensimultaneously exhibit antidepressive, anxiolytic, and analgesiceffects, and thereby provide good news to patients suffered fromdepression, anxiety, and pain. A further object of the present inventionis to provide a medicament that can be used for simultaneously treatingdepression, anxiety, and pain as single medicament, and that can be safeand administered orally or by injection (for example, subcutaneousinjection).

Means for Solving the Problem

(1) The present invention relates to a compound represented by thefollowing general formula (I):

(wherein R¹ represents hydrogen; C₁₋₁₀ alkyl; C₆₋₁₀ aryl; C₂₋₆ alkenyl;cycloalkylalkyl where the cycloalkyl moiety has 3 to 6 carbon atoms, andthe alkylene moiety has 1 to 5 carbon atoms; aralkyl where the arylmoiety has 6 to 10 carbon atoms, and the alkylene moiety has 1 to 5carbon atoms; C₃₋₆ cycloalkyl; or heteroarylalkyl where the heteroarylmoiety contains 1 to 4 heteroatoms selected from N, O and S asring-constituting atoms, and the alkylene moiety has 1 to 5 carbonatoms,

R² represents heterocyclic ring containing 1 to 4 heteroatoms selectedfrom N, O and S and at least one carbon atom as ring-constituting atoms,containing at least one set of adjacent ring-constituting atoms bound bya double bond, and further substituted with at least one oxo group,

R² binds to Y via a carbon atom as a ring-constituting atom of R²,

R³, R⁴, and R⁵, which are the same or different, represent hydrogen;hydroxy; halogen; cyano; carbamoyl; C₁₋₆ alkoxy; C₆₋₁₀ aryloxy; C₁₋₆alkanoyloxy; nitro; amino; C₁₋₅ alkylamino; C₆₋₁₀ arylamino; oracylamino where the acyl moiety has 2 to 6 carbon atoms,

R^(6a) and R^(6b), which are the same or different, represent hydrogen;fluorine; or hydroxy, or R^(6a) and R^(6b) combine together torepresent═O,

R⁷ and R⁸, which are the same or different, represent hydrogen;fluorine; or hydroxy,

R⁹ and R¹⁰, which are the same or different, represent hydrogen; C₁₋₆alkyl; Cei aryl; heteroaryl containing 1 to 4 heteroatoms selected fromN, O and S as ring-constituting atoms; aralkyl where the aryl moiety has6 to 10 carbon atoms, and the alkylene moiety has 1 to 5 carbon atoms;heteroarylalkyl where the heteroaryl moiety contains 1 to 4 heteroatomsselected from N, O and S as ring-constituting atoms, and the alkylenemoiety has 1 to 5 carbon atoms; cycloalkylalkyl where the cycloalkylmoiety has 3 to 6 carbon atoms, and the alkylene moiety has 1 to 5carbon atoms; or C₂₋₆ alkenyl,

X represents O or CH₂, and

Y represents C(═O),

provided that the C₁₋₁₀ alkyl as R¹; the alkylene moiety and cycloalkylmoiety of the cycloalkylalkyl where the cycloalkyl moiety has 3 to 6carbon atoms, and the alkylene moiety has 1 to 5 carbon atoms as R¹; thealkylene moiety of the aralkyl where the aryl moiety has 6 to 10 carbonatoms, and the alkylene moiety has 1 to 5 carbon atoms as R¹; and thealkylene moiety of the heteroarylalkyl where the heteroaryl moietycontains 1 to 4 heteroatoms selected from N, O and S asring-constituting atoms, and the alkylene moiety has 1 to 5 carbon atomsas R¹ may be substituted with at least one substituent selected from

1 to 6 halogens; hydroxy, C₁₋₆ alkoxy; C₆₋₁₀ aryloxy; C₁₋₆ alkanoyl;C₁₋₆ alkanoyloxy; carboxyl; alkoxycarbonyl where the alkoxy moiety has 1to 6 carbon atoms; carbamoyl; alkylcarbamoyl where the alkyl moiety has1 to 6 carbon atoms; dialkylcarbamoyl where each alkyl moiety has 1 to 6carbon atoms; alkylsulfonyl where the alkyl moiety has 1 to 6 carbonatoms; aminosulfonyl; alkylsulfinyl where the alkyl moiety has 1 to 6carbon atoms; alkylthio where the alkyl moiety has 1 to 6 carbon atoms;C₁₋₆ alkoxy substituted with 1 to 6 halogens; and arylcarbonyl where thearyl moiety has 6 to 10 carbon atoms,

the C₆₋₁₀ aryl as R¹; the aryl moiety of the aralkyl where the arylmoiety has 6 to 10 carbon atoms, and the alkylene moiety has 1 to 5carbon atoms as R¹; the aryl moiety of the C₆₋₁₀ aryloxy as R³, R⁴, orR⁵; the aryl moiety of the C₆₋₁₀ arylamino as R³, R⁴, or R⁵; the C₆₋₁₀aryl as R⁹ or R¹⁰; the heteroaryl containing 1 to 4 heteroatoms selectedfrom N, O and S as ring-constituting atoms as R⁹ or R¹⁰; the aryl moietyof the aralkyl where the aryl moiety has 6 to 10 carbon atoms, and thealkylene moiety has 1 to 5 carbon atoms as R⁹ or R¹⁰; and the heteroarylmoiety of the heteroarylalkyl where the heteroaryl moiety contains 1 to4 heteroatoms selected from N, O and S as ring-constituting atoms, andthe alkylene moiety has 1 to 5 carbon atoms as R¹ or R¹⁰ may besubstituted with at least one substituent selected from

C₁₋₆ alkyl; C₁₋₆ alkoxy; C₁₋₆ alkanoyloxy; hydroxy; alkoxycarbonyl wherethe alkoxy moiety has 1 to 6 carbon atoms; carbamoyl; alkylcarbamoylwhere the alkyl moiety has 1 to 6 carbon atoms; dialkylcarbamoyl whereeach alkyl moiety has 1 to 6 carbon atoms; halogen; nitro; cyano; C₁₋₆alkyl substituted with 1 to 3 halogens; C₁₋₆ alkoxy substituted with 1to 3 halogens; phenyl; heteroaryl containing 1 to 4 heteroatoms selectedfrom N, O and S as ring-constituting atoms; phenoxy; phenylalkyl wherethe alkyl has 1 to 3 carbon atoms; and methylenedioxy,

the heterocyclic ring as R² may have, besides the oxo group, thesubstituents that the C₆₋₁₀ aryl as R¹ mentioned above may have,

when R¹ is C₁₋₁₀ alkyl, it may be substituted with NR¹¹R¹², where R¹¹and R¹², which are the same or different, represent hydrogen; C₁₋₁₀alkyl; or aralkyl where the aryl moiety has 6 to 10 carbon atoms, andthe alkylene moiety has 1 to 6 carbon atoms; or R¹¹, R¹², the nitrogenatom to which R¹¹ and R¹² bind, and optionally, 1 or 2 heteroatoms maycombine together to form a 6- to 7-membered ring, and the alkylenemoiety of the aralkyl where the aryl moiety has 6 to 10 carbon atoms,and the alkylene moiety has 1 to 5 carbon atoms as R¹ may be substitutedwith at least one substituent selected from phenyl, and C₁₋₆ alkylsubstituted with 1 to 3 halogens),

a tautomer or stereoisomer of the compound, or a pharmaceuticallyacceptable salt thereof, or a solvate thereof.

The present invention also relates to a medicament comprising a compoundrepresented by the aforementioned general formula (I), a tautomer orstereoisomer of the compound, or a pharmaceutically acceptable saltthereof, or a solvate thereof.

The present invention also relates to a pharmaceutical compositioncomprising a compound represented by the aforementioned general formula(I), a tautomer or stereoisomer of the compound, or a pharmaceuticallyacceptable salt thereof, or a solvate thereof as an active ingredient.

The present invention also relates to an analgesic comprising a compoundrepresented by the aforementioned general formula (I), a tautomer orstereoisomer of the compound, or a pharmaceutically acceptable saltthereof, or a solvate thereof as an active ingredient.

The present invention also relates to an antidepressant comprising acompound represented by the aforementioned general formula (I), atautomer or stereoisomer of the compound, or a pharmaceuticallyacceptable salt thereof, or a solvate thereof as an active ingredient.

The present invention also relates to an anxiolytic drug comprising acompound represented by the aforementioned general formula (I), atautomer or stereoisomer of the compound, or a pharmaceuticallyacceptable salt thereof, or a solvate thereof as an active ingredient.

The present invention also relates to a method for ameliorating,preventing or treating depression, which comprises administering aneffective amount of a compound represented by the aforementioned generalformula (I), a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof.

The present invention also relates to a method for ameliorating,preventing or treating anxiety, which comprises administering aneffective amount of a compound represented by the aforementioned generalformula (I), a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof.

The present invention also relates to a method for ameliorating,preventing or treating pain, which comprises administering an effectiveamount of a compound represented by the aforementioned general formula(I), a tautomer or stereoisomer of the compound, or a pharmaceuticallyacceptable salt thereof, or a solvate thereof.

The present invention also relates to use of a compound represented bythe aforementioned general formula (I), a tautomer or stereoisomer ofthe compound, or a pharmaceutically acceptable salt thereof, or asolvate thereof for ameliorating, preventing or treating pain,depression, or anxiety.

The present invention also relates to a method for ameliorating,preventing or treating pain, depression, or anxiety in a human, whichcomprises administering an effective amount of a compound represented bythe aforementioned general formula (I), a tautomer or stereoisomer ofthe compound, or a pharmaceutically acceptable salt thereof, or asolvate thereof to the human.

The present invention also relates to a therapeutic agent forParkinson's disease comprising a compound represented by theaforementioned general formula (I), a tautomer or stereoisomer of thecompound, or a pharmaceutically acceptable salt thereof, or a solvatethereof as an active ingredient.

The present invention also relates to a method for ameliorating,preventing or treating Parkinson's disease, which comprisesadministering an effective amount of a compound represented by theaforementioned general formula (I), a tautomer or stereoisomer of thecompound, or a pharmaceutically acceptable salt thereof, or a solvatethereof.

The present invention also relates to use of a compound represented bythe aforementioned general formula (I), a tautomer or stereoisomer ofthe compound, or a pharmaceutically acceptable salt thereof, or asolvate thereof for ameliorating, preventing or treating Parkinson'sdisease.

The present invention also relates to a method for ameliorating,preventing or treating Parkinson's disease in a human, which comprisesadministering an effective amount of a compound represented by theaforementioned general formula (I), a tautomer or stereoisomer of thecompound, or a pharmaceutically acceptable salt thereof, or a solvatethereof to the human.

The present invention also relates to a therapeutic agent forpollakiuria or urinary incontinence comprising a compound represented bythe aforementioned general formula (I), a tautomer or stereoisomer ofthe compound, or a pharmaceutically acceptable salt thereof, or asolvate thereof as an active ingredient.

The present invention also relates to a method for ameliorating,preventing or treating pollakiuria or urinary incontinence, whichcomprises administering an effective amount of a compound represented bythe aforementioned general formula (I), a tautomer or stereoisomer ofthe compound, or a pharmaceutically acceptable salt thereof, or asolvate thereof.

The present invention also relates to use of a compound represented bythe aforementioned general formula (I), a tautomer or stereoisomer ofthe compound, or a pharmaceutically acceptable salt thereof, or asolvate thereof for ameliorating, preventing or treating pollakiuria orurinary incontinence.

The present invention also relates to a method for ameliorating,preventing or treating pollakiuria or urinary incontinence in a human,which comprises administering an effective amount of a compoundrepresented by the aforementioned general formula (I), a tautomer orstereoisomer of the compound, or a pharmaceutically acceptable saltthereof, or a solvate thereof to the human.

The present invention also relates to a therapeutic agent for glaucomacomprising a compound represented by the aforementioned general formula(I), a tautomer or stereoisomer of the compound, or a pharmaceuticallyacceptable salt thereof, or a solvate thereof as an active ingredient.

The present invention also relates to a method for ameliorating,preventing or treating glaucoma, which comprises administering aneffective amount of a compound represented by the aforementioned generalformula (I), a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof.

The present invention also relates to use of a compound represented bythe aforementioned general formula (I), a tautomer or stereoisomer ofthe compound, or a pharmaceutically acceptable salt thereof, or asolvate thereof for ameliorating, preventing or treating glaucoma.

The present invention also relates to a method for ameliorating,preventing or treating glaucoma in a human, which comprisesadministering an effective amount of a compound represented by theaforementioned general formula (I), a tautomer or stereoisomer of thecompound, or a pharmaceutically acceptable salt thereof, or a solvatethereof to the human.

Effect of the Invention

The compounds represented by the general formula (I), tautomers orstereoisomers of the compounds, pharmaceutically acceptable saltsthereof, and solvates thereof, which are the compounds provided by thepresent invention, exhibit potent agonistic activity for the opioid δreceptor, but do not activate or only extremely weakly activate the μand κ receptors, and therefore they have superior antidepressiveeffects, anxiolytic effects, analgesic effects, therapeutic effects forParkinson's disease, and therapeutic effects for pollakiuria and urinaryincontinence based on activation of the opioid δ receptor. Since thecompounds of the present invention do not activate or only extremelyweakly activate the μ and κ receptors, they do not provide or extremelyweakly provide adverse effects such as dependence, drug abuse,tolerance, respiratory depression, constipation caused by suppression ofgastrointestinal motility, nausea and vomiting, blood pressurereductions, bradycardia, cough reflex inhibition, sleepiness, sweating,and thirst. As far as the inventors of the present invention examined,the compounds of the present invention do not act on or extremely weaklyact on other receptors, channels, and enzymes. Therefore, it is expectedthat the compounds of the present invention do not show at all orextremely weakly show adverse effects such as convulsion, musclerelaxation, sedation, and cognitive function decline.

Since high blood concentration and enhanced migration into the brain ofthe compounds of the present invention are achieved by oraladministration or administration by injection (for example, subcutaneousinjection), they can be used by oral administration or administration byinjection.

Since the compounds of the present invention are hardly metabolized inthe microsomes derived from hepatocytes, they are advantageous from theviewpoint of drug metabolism. They impose little risk of adverse effectscaused by metabolic products, either.

The compounds of the present invention do not show at all any inhibitoryactivity against Kv11.1 (or hERG, human ether-a-go-go related gene),which is the potassium ion channel responsible to the repolarisation ofmyocardial action potential, or show such an inhibitory activity at anignorable level, and therefore they are safe drugs in respect of risk ofsudden death caused by prolongation of the QT interval.

The compounds of the present invention are highly effective and safemedicaments.

The compounds of the present invention can simultaneously eliminate allof depression, anxiety, and pain as a single medicament.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph showing the results of the mouse elevated plus mazetest for the compound 1.

FIG. 2 is a graph showing the results of the mouse elevated plus mazetest for the compound 7.

FIG. 3 is a graph showing the results of the mouse elevated plus mazetest for the compound 3.

FIG. 4 is a graph showing the results of the mouse elevated plus mazetest for the compound 9.

FIG. 5 is a graph showing the results of the mouse elevated plus mazetest for the compound 10.

FIG. 6 is a graph showing the results of the rat elevated plus mas testfor the compounds 3, 7, and 10.

MODE FOR CARRYING OUT THE INVENTION

Hereafter, the present invention will be explained in more detail.

Preferred embodiments of the compound represented by the aforementionedgeneral formula (I), a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto (1) include the followings.

(2) The compound represented by the aforementioned general formula (I),a tautomer or stereoisomer of the compound, or a pharmaceuticallyacceptable salt thereof, or a solvate thereof according to (1), whereinR¹ is C₁₋₁₀ alkyl; cycloalkylalkyl where the cycloalkyl moiety has 3 to6 carbon atoms, and the alkylene moiety has 1 to 5 carbon atoms; oraralkyl where the aryl moiety has 6 to 10 carbon atoms, and the alkylenemoiety has 1 to 5 carbon atoms.(3) The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto (1) or (2) mentioned above, wherein R¹ is cycloalkylalkyl where thecycloalkyl moiety has 3 to 6 carbon atoms, and the alkylene moiety has 1to 5 carbon atoms.(4) The compound represented by the aforementioned general formula (I),a tautomer or stereoisomer of the compound, or a pharmaceuticallyacceptable salt thereof, or a solvate thereof according to (1), whereinR¹ is C₂₋₆ alkyl substituted with hydroxy; C₁₋₆ alkyl substituted with 1to 6 halogens; or C₂₋₆ alkyl substituted with C₁₋₆ alkoxy.(5) The compound represented by the aforementioned general formula (I),a tautomer or stereoisomer of the compound, or a pharmaceuticallyacceptable salt thereof, or a solvate thereof according to (1), whereinR¹ is allyl, fluoropropyl, 2-(pyridin-3-yl)ethyl,2-(methylsulfonyl)ethyl, or 2-(aminosulfonyl)ethyl.(6) The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof, whereinaccording to any one of (1) to (5) mentioned above, wherein R² is a 5-to 7-membered heterocyclic ring containing 1 to 4 heteroatoms selectedfrom N, O and S and at least one carbon atom as ring-constituting atoms,containing at least one set of adjacent ring-constituting atoms bound bya double bond, and further substituted with at least one oxo group; or aheterocyclic ring consisting of the foregoing heterocyclic ring and abenzene ring condensed thereto.(7) The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto any one of (1) to (6) mentioned above, wherein R² is pyridine1-oxide, which may be substituted with 1 to 4 substituents selected fromC₁₋₁₀ alkyl substituted with 1 to 3 fluorine atoms, and unsubstitutedC₁₋₁₀ alkyl.(8) The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto any one of (1) to (7) mentioned above, wherein R² is pyridine1-oxide.(9) The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto any one of (1) to (6) mentioned above, wherein R² ispyridin-2(1H)-one, which may be substituted with 1 to 4 substituentsselected from C₁₋₁₀ alkyl substituted with 1 to 3 fluorine atoms, andunsubstituted C₁₋₁₀ alkyl.(10) The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto any one of (1) to (6), and (9) mentioned above, wherein R² ispyridin-2(1H)-one; 1-(C₁₋₆ alkyl)pyridin-2(1H)-one; or 6-(C₁₋₆alkyl)pyridin-2(4H)-one.(11) The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto any one of (1) to (6) mentioned above, wherein R² ispyridin-4(1H)-one, which may be substituted with 1 to 4 substituentsselected from C₁₋₁₀ alkyl substituted with 1 to 3 fluorine atoms, andunsubstituted C₁₋₁₀ alkyl.(12) The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto any one of (1) to (6), and (11) mentioned above, wherein R ispyridin-4(1H)-one, or 1-(C₁₋₆ alkyl)pyridin-4(1H)-one.(13) The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto any one of (1) to (6) mentioned above, wherein R² ispyridazin-3(2H)-one, which may be substituted with 1 to 3 substituentsselected from C₁₋₁₀ alkyl substituted with 1 to 3 fluorine atoms, andunsubstituted C₁₋₁₀ alkyl.(14) The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto any one of (1) to (6), and (13) mentioned above, wherein R² ispyridazin-3(2H)-one.(15) The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto any one of (1) to (6) mentioned above, wherein R² ispyrazin-2(1H)-one, which may be substituted with 1 to 3 substituentsselected from C₁₋₁₀ alkyl substituted with 1 to 3 fluorine atoms, andunsubstituted C₁₋₁₀ alkyl.(16) The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto any one of (1) to (6) mentioned above, wherein R² ispyrazin-2(1H)-one.(17) The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto any one of (1) to (6) mentioned above, wherein R² is 4H-pyran-4-one,or 2H-pyran-2-one, which may be substituted with 1 to 3 substituentsselected from C₁₋₁₀ alkyl substituted with 1 to 3 fluorine atoms, andunsubstituted C₁₋₁₀ alkyl.(18) The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto any one of (1) to (6), and (17) mentioned above, wherein R² is4H-pyran-4-one, or 2H-pyran-2-one.(19) The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto any one of (1) to (6) mentioned above, wherein R² isquinolin-2(1H)-one, which may be substituted with 1 to 3 substituentsselected from C₁₋₁₀ alkyl substituted with 1 to 8 fluorine atoms, andunsubstituted C₁₋₁₀ alkyl.(20) The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto any one of (1) to (6) mentioned above, wherein R² isquinolin-2(1H)-one.(21) The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto any one of (1) to (6) mentioned above, wherein R² ispyrimidin-4(3H)-one, or pyrimidine-2,4(1H,3H)-dione, which may besubstituted with 1 to 3 substituents selected from C₁₋₁₀ alkylsubstituted with 1 to 3 fluorine atoms, and unsubstituted C₁₋₁₀ alkyl.(22) The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto any one of (1) to (6), and (21) mentioned above, wherein R² ispyrimidin-4(3H)-one, or pyrimidine-2,4(1H,3H)-dione.(23) The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto any one of (1) to (22) mentioned above, wherein X is CH₂.(24) The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof or a solvate thereof accordingto any one of (1) to (23) mentioned above, wherein one of R³ and R⁴ ishydrox, and the other is hydrogen.(25) The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto any one of (1) to (23) mentioned above, wherein R³ is halogen; cyano;carbamoyl; C₁₋₆ alkoxy; C₁₋₆ alkanoyloxy; amino; or acylamino where theacyl moiety has 2 to 6 carbon atoms, R⁴ is hydrogen or hydroxy, and R⁵is hydrogen.(26) The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto any one of (1) to (23) mentioned above, wherein R³ is hydroxy;carbamoyl; or C₁₋₆ alkanoyloxy, R⁴ is hydrogen, and R⁵ is hydrogen.(27) The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto any one of (1) to (23) mentioned above, wherein R³ is hydroxy, R⁴ ishydrogen, and R⁸ is hydrogen.(28) The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto any one of (1) to (23) mentioned above, wherein all of R³, R⁴, and R⁵are hydrogens.(29) The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto any one of (1) to (28) mentioned above, wherein all of R^(6a),R^(6b), R⁷, R⁸, R⁹, and R¹⁰ are hydrogens.(30) The compound represented by the aforementioned general formula (I),a tautomer or stereoisomer of the compound, or a pharmaceuticallyacceptable salt thereof, or a solvate thereof according to (1), wherein:

R⁵, R^(6a), R^(6b), R⁷, R⁸, R⁹, and R¹⁰ are hydrogens,

R¹ is hydrogen; C₁₋₆ alkyl; C₂₋₆ alkenyl; cycloalkylalkyl where thecycloalkyl moiety has 3 to 6 carbon atoms, and the alkylene moiety has 1to 5 carbon atoms; or aralkyl where the aryl moiety has 6 to 10 carbonatoms, and the alkylene moiety has 1 to 5 carbon atoms.

R² is a 5- to 7-membered heterocyclic ring containing 1 to 4 heteroatomsselected from N, O and S and at least one carbon atom asring-constituting atoms, containing at least one set of adjacentring-constituting atoms bound by a double bond, and further substitutedwith at least one oxo group, or a heterocyclic ring consisting of theforegoing heterocyclic ring and a benzene ring condensed thereto,

R² binds to Y via a carbon atom of R² as a ring-constituting atom,

R³ and R⁴, which are the same or different, represent hydrogen; hydroxy;halogen; cyano; carbamoyl; C₁₋₆ alkoxy; C₆₋₁₀ aryloxy; C₁₋₆ alkanoyloiy;amino; or acylamino where the acyl moiety has 2 to 6 carbon atoms,

X is CH₂, and

Y is C(═O),

provided that the C₁₋₆ alkyl as R¹; the alkylene moiety and cycloalkylmoiety of the cycloalkylalkyl where the cycloalkyl moiety has 3 to 6carbon atoms, and the alkylene moiety has 1 to 5 carbon atoms as R¹; andthe alkylene moiety of the aralkyl where the aryl moiety has 6 to 10carbon atoms, and the alkylene moiety has 1 to 5 carbon atoms as R, maybe substituted with at least one substituent selected from

1 to 6 halogens; hydroxy; C₁₋₆ alkoxy; C₆₋₁₀ aryloxy; C₁₋₆ alkanoyl;C₁₋₆ alkanoyloxy; carboxyl; alkoxycarbonyl where the alkoxy moiety has 1to 6 carbon atoms; carbamoyl; alkylcarbamoyl where the alkyl moiety has1 to 6 carbon atoms; dialkylcarbamoyl where each alkyl moiety has 1 to 6carbon atoms; alkylsulfonyl where the alkyl moiety has 1 to 6 carbonatoms; aminosulfonyl; alkylsulfinyl where the alkyl moiety has 1 to 6carbon atoms; alkylthio where the alkyl moiety has 1 to 6 carbon atoms;C₁₋₆ alkoxy substituted with 1 to 6 halogens; and arylcarbonyl where thearyl moiety has 6 to 10 carbon atoms,

the aryl moiety of the aralkyl where the aryl moiety has 6 to 10 carbonatoms, and the alkylene moiety has 1 to 6 carbon atoms as R¹; and thearyl moiety of the C₆₋₁₀ aryloxy as R³ or R⁴ may be substituted with atleast one substituent selected from

C₁₋₆ alkyl; C₁₋₆ alkoxy; C₁₋₆ alkanoyloxy; hydroxy; alkoxycarbonyl wherethe alkoxy moiety has 1 to 6 carbon atoms; carbamoyl; alkylcarbamoylwhere the alkyl moiety has 1 to 6 carbon atoms; dialkylcarbamoyl whereeach alkyl moiety has 1 to 6 carbon atoms; halogen; nitro; cyano; C₁₋₆alkyl substituted with 1 to 3 halogens; C₁₋₆ alkoxy substituted with 1to 3 halogens; phenyl; heteroaryl containing 1 to 4 heteroatoms selectedfrom N, O and S as ring-constituting atoms; phenoxy; phenylalkyl wherethe alkyl has 1 to 3 carbon atoms; and methylenedioxy,

the heterocyclic ring as RX may have, besides the oxo group, at leastone of the substituents which the aryl moiety of the aralkyl where thearyl moiety has 6 to 10 carbon atoms, and the alkylene moiety has 1 to 5carbon atoms as R¹ may have, and

the alkylene moiety of the aralkyl where the aryl moiety has 6 to 10carbon atoms, and the alkylene moiety has 1 to 6 carbon atoms as R² maybe substituted with at least one substituent selected from phenyl, andC₁₋₆ alkyl substituted with 1 to 3 halogens.

(31) The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto (1) or (30), wherein R¹ is C₁₋₆ alkyl; cycloalkylalkyl where thecycloalkyl moiety has 3 to 6 carbon atoms, and the alkylene moiety has 1to 5 carbon atoms; or aralkyl where the aryl moiety has 6 to 10 carbonatoms, and the alkylene moiety has 1 to 6 carbon atoms.(32) The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto (1), (30), or(31), wherein R¹ is cycloalkylalkyl where the cycloalkyl moiety has 3 to6 carbon atoms, and the alkylene moiety has 1 to 6 carbon atoms.(33) The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto (1) or (30), wherein R¹ is C₂₋₆ alkyl substituted with hydroxy; C₁₋₆alkyl substituted with 1 to 6 halogens; or C₂₋₆ alkyl substituted withC₁₋₆ alkoxy.(34) The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto (1) or (30), wherein R¹ is allyl, fluoropropyl,2-(pyridin-3-yl)ethyl, 2-(methylsulfonyl)ethyl, or2-(aminosulfonyl)ethyl.(35) The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto any one of (1), and (30) to (34), wherein R² is pyridine 1-oxide,pyridin-2(1H)-one, pyridin-4(1H)-one, pyridazin-3(2H)-one,pyrazin-2(1H)-one, 4H-pyran-4-one, 2H-pyran-2-one, quinolin-2(1H)-one,pyrimidin-4(3H)-one, or pyrimidine-2,4(1H,3H)-dione, which may besubstituted with a substituent selected from C₁₋₁₀ alkyl substitutedwith 1 to 3 fluorine atoms, and unsubstituted C₁₋₁₀ alkyl.(36) The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto any one of (1), and (30) to (35), wherein R² is pyridine 1-oxide,which may be substituted with 1 to 4 substituents selected from C₁₋₁₀alkyl substituted with 1 to 3 fluorine atoms, and unsubstituted C₁₋₁₀alkyl.(37) The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto any one of (1), and (30) to (36), wherein R² is pyridine 1-oxide.(38) The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto any one of (1), and (30) to (35), wherein R² is pyridin-2(1H)-one,which may be substituted with 1 to 4 substituents selected from C₁₋₁₀alkyl substituted with 1 to 3 fluorine atoms, and unsubstituted C₁₋₁₀alkyl.(39) The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto any one of (1), and (30) to (35), wherein R² is pyridin-2(1H)-one;1-(C₁₋₅ alkyl)pyridin-2(1H)-one; or 6-(C₁₋₆ alky)pyridin-2(1H)-one.(40) The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto any one of (1), and (30) to (35), wherein R² is pyridin-4(1H)-one,which may be substituted with 1 to 4 substituents selected from C₁₋₁₀alkyl substituted with 1 to 3 fluorine atoms, and unsubstituted C₁₋₁₀alkyl.(41) The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto any one of (1), (30) to (35), and (40), wherein R² ispyridin-4(1H)-one, or 1-(C₁₋₆ alkyl)pyridin-4(1H)-one.(42) The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto any one of (0, and (30) to (35), wherein R² is pyridazin-3(2H)-one,which may be substituted with 1 to 3 substituents selected from C₁₋₁₀alkyl substituted with 1 to 3 fluorine atoms, and unsubstituted C₁₋₁₀alkyl.(43) The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto any one of (1), (30) to (35), and (42), wherein R² ispyridazin-3(2H)-one.(44) The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto any one of (1), and (30) to (35), wherein R² is pyrazin-2(1H)-one,which may be substituted with 1 to 3 substituents selected from C₁₋₁₀alkyl substituted with 1 to 3 fluorine atoms, and unsubstituted C₁₋₁₀alkyl.(46) The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto any one of (1), (30) to (35), and (44), wherein R² ispyrazin-2(1H)-one.(48) The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto any one of (1), and (30) to (35), wherein R² is 4H-pyran-4-one, or2H-pyran-2-one, which may be substituted with 1 to 3 substituentsselected from C₁₋₁₀ alkyl substituted with 1 to 3 fluorine atoms, andunsubstituted C₁₋₁₀ alkyl.(47) The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto any one of (1), (30) to (36), and (46), wherein R² is 4H-pyran-4-one,or 2H-pyran-2-one.(48) The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto any one of (1), and (30) to (35), wherein R² is quinolin-2(1H)-one,which may be substituted with 1 to 3 substituents selected from C₁₋₁₀alkyl substituted with 1 to 3 fluorine atoms, and unsubstituted C₁₋₁₀alkyl.(49) The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto any one of (1), (30) to (35), and (48), wherein R² isquinolin-2(1H)-one.(50) The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto any one of (1), and (30) to (35), wherein R² is pyrimidin-4(3H)-one,or pyrimidine-2,4(1H,3H) dione, which may be substituted with 1 to 3substituents selected from C₁₋₁₀ alkyl substituted with 1 to 3 fluorineatoms, and unsubstituted C₁₋₁₀ alkyl.(51 The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto any one of (1), (30) to (35), and (60), wherein R² ispyrimidin-4(3H)-one, or pyrimidine-2,4(1H,3H)-dione.(52) The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto any one of (1), and (30) to (51), wherein one of R³ and R⁴ ishydroxy, and the other is hydrogen.(63) The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto any one of (1), and (30) to (51), wherein R³ is halogen; cyano;carbamoyl; C₁₋₆ alkoxy; C₁₋₆ alkanoyloxy; amino; or acylamino where theacyl moiety has 2 to 6 carbon atoms, and R⁴ is hydrogen or hydroxy.(54) The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto any one of (1), and (30) to (51), wherein R³ is hydroxy; carbamoyl;or C₁₋₆ alkanoyloxy, and R⁴ is hydrogen.(65) The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto any one of (1), and (30) to (51), wherein R³ is hydroxy, and R⁴ ishydrogen.(56) The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto any one of (1), and (30) to (51), wherein Ra and R⁴ are hydrogens.(57) A compound selected from:

-   2-((1S,3aR,5aS,6B,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine    1-oxide,-   4-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine    1-oxide,-   3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one,-   3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine    1-oxide,-   5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one,-   3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy    2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one,-   6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one,-   3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy    2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-6-methylpyridin-2(1H)-one,-   5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one,-   6-((1S,3&R,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one,-   4-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one,-   5-((1S,8aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyrimidine-2,4(1H,3H)-dione,-   3-((1S,3aR,5aS,6R,11bR,11cS)-14-(Cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-4(1H)-one,-   2-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-4(1H)-one,-   4-((1S,3aR,6aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-methylpyridin-2(1H)-one,-   6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridazin-8(2H)-one,-   4-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)quinolin-2(1H)-one,-   5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-2H-pyran-2-one,-   2-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy    2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-4H-pyran-4-one,-   2-((1S,3aR,6aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-4(1H)-one,-   5-((1S,3aR,6aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyrazin-2(1H)-one,-   2-((1S,3aR,5aS,6R,11bR,11cS)-10-acetoxy-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine    1-oxide,-   6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one,-   3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyrazin-2(1H)-one,-   6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyrimidine-2,4(1H,3H)-dione,-   6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-ethylpyridin-2(11)-one,-   6-((1S,3aR,6aS,6R,11bR,1cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,1c-octahydro-11H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyrimidin-4(3H)-one,    and-   5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-ethylpyridin-2(1H)-one,    a tautomer or stereoisomer of the compound, or a pharmaceutically    acceptable salt thereof, or a solvate thereof.-   (58) A compound selected from:-   6-((1S,3aR,5aS,6R,11bR,11cS)    10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(110-one,-   4-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methyl-1,2-dihydro-3H-pyrazol-3-one,-   5-chloro-3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)    10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one,-   5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1,3-dimethylpyrimidine-2,4(1H),    3-dione, and-   6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-methoxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one,    a tautomer or stereoisomer of the compound, or a pharmaceutically    acceptable salt thereof, or a solvate thereof.

As used herein:

Examples of the C₁₋₆ alkyl include methyl, ethyl, propyl, i-propyl,butyl, t-butyl, pentyl, neopentyl, hexyl, and the like.

Examples of the C₁₋₁₀ alkyl include those exemplified for the C₁₋₆alkyl, as well as heptyl, octyl, and the like.

Examples of the C₁₋₆ alkyl substituted with 1 to 3 halogens include2-chloroethyl, 2-fluoroethyl, 3-fluoropropyl, 2,2-difluoroethyl,trifluoromethyl, 3,3,3-trifluoropropyl, and the like.

Examples of the C₂₋₆ alkenyl include 2-propenyl, 3-methyl-2-butenyl, andthe like.

Examples of the cycloalkylalkyl where the cycloalkyl moiety has 3 to 6carbon atoms, and the alkylene moiety has 1 to 6 carbon atoms includemethyl, ethyl, and the like substituted with C₃₋₆ cycloalkyl such ascyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

Examples of the aralkyl where the aryl moiety has 6 to 10 carbon atoms,and the alkylene moiety has 1 to 5 carbon atoms include benzyl group,and phenethyl group.

Examples of the C₃₋₆ cycloalkyl include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, and the like.

Examples of the C₆₋₁₀ aryl include phenyl, naphthyl, and the like.

Examples of the heteroaryl containing 1 to 4 heteroatoms selected fromN. O and 8 as ring-constituting atoms include pyridyl, furyl,imidazolyl, pyrazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolyl,and the like.

Examples of the heteroarylalkyl where the heteroaryl moiety contains 1to 4 heteroatoms selected from N, O and S as ring-constituting atoms,and the alkylene moiety has 1 to 5 carbon atoms include(pyridin-2-yl)methyl, (pyridin-3-yl)methyl, (pyridin-4-yl)methyl,(furan-2-yl)methyl, (furan-8-yl)methyl, (imidazol-2-yl)methyl,(imidazol-4-yl)methyl, (imidazol-5-yl)methyl, (thiazol-2-yl)methyl,(thiazol-4-yl)methyl, (thiazol-5-yl)methyl, 2-(pyridin-27l)ethyl,2-(pyridin-3-yl)ethyl, 2-(pyrazol-1-ylethyl, 2-(thiophen-2-yl)ethyl,2-(thiophen-3-yl)ethyl, and the like.

Examples of the C₁₋₆ alkanoyl include acetyl, propionyl, and the like.

Examples of the C₁₋₆ alkoxy include methoxy, ethoxy, propoxy, and thelike.

Examples of the C₁₋₆ alkanoyloxy include acetoxy, and the like.

Examples of the alkoxycarbonyl where the alkoxy moiety has 1 to 6 carbonatoms include methoxycarbonyl, ethoxycarbonyl, and the like.

Examples of the halogen include fluorine, chlorine, bromine, iodine, andthe like.

Examples of the C₁₋₆ alkoxy substituted with 1 to 3 halogens includefluoromethoxy, trifluoromethoxy, and the like.

Examples of the C₁₋₆ alkoxy substituted with 1 to 6 halogens includethose mentioned above for the C₁₋₆ alkoxy substituted with 1 to 3halogens, as well as tetrafluoroethoxy, and the like.

Examples of the phenylalkyl where the alkyl has 1 to 3 carbon atomsinclude benzyl, and the like.

Examples of the C₆₋₁₀ aryloxy include phenoxy, and the like.

Examples of the C₁₋₈ alkylamino include methylamino, ethylamino, and thelike.

Examples of the acylamino where the acyl moiety has 2 to 6 carbon atomsinclude acetylamino, and the like.

Examples of the C₆₋₁₀ arylamino include phenylamino, and the like.

Examples of the alkylcarbamoyl where the alkyl moiety has 1 to 6 carbonatoms include ethylcarbamoyl, and the like.

Examples of the dialkylcarbamoyl where each alkyl moiety has 1 to 6carbon atoms include diethylcarbamoyl, and the like.

Examples of the alkylsulfonyl where the alkyl moiety has 1 to 6 carbonatoms include methylsulfonyl, and the like.

Examples of the alkylsulfinyl where the alkyl moiety has 1 to 6 carbonatoms include methylsulfinyl, and the like.

Examples of the alkylthio where the alkyl moiety has 1 to 6 carbon atomsinclude methylthio, and the like.

Examples of the arylcarbonyl where the aryl moiety has 6 to 10 carbonatoms include benzoyl, and the like.

Examples of the 6- to 7-membered ring that may be formed by combiningR¹¹, R¹² together with the nitrogen atom to which R¹¹ and R¹² bind, andoptionally, 1 or 2 heteroatoms include pyrrolidine, piperidine,morpholine, and the like.

Examples of the heterocyclic ring containing 1 to 4 heteroatoms selectedfrom N, O and S and at least one carbon atom as ring-constituting atoms,containing at least one set of adjacent ring-constituting atoms bound bya double bond, and further substituted with at least one oxo group as R²include:

(A) pyridine 1-oxide, which may be substituted with 1 to 4 substituentsselected from C₁₋₁₀ alkyl substituted with 1 to 3 fluorine atoms, andunsubstituted C₁₋₁₀ alkyl: for example, pyridine 1-oxide and2-methylpyridine 1-oxide;

(B) pyridin-2(4H)-one, which may be substituted with 1 to 4 substituentsselected from C₁₋₁₀ alkyl substituted with 1 to 3 fluorine atoms, andunsubstituted C₁₋₁₀ alkyl: for example, pyridin-2(1H)-one,1-methylpyridin-2(1H)-one, 1-ethylpyridin-2(1H)-one,6-methylpyridin-2(0H)-one, 6-ethylpyridin-2(1H)-one, and6-trifluoromethylpyridin-2(1H)-one;

(C) pyridin-4(0H)-one, which may be substituted with 1 to 4 substituentsselected from C₁₋₁₀ alkyl substituted with 1 to 3 fluorine atoms, andunsubstituted C₁₋₁₀ alkyl: for example, pyridin-4(1H)-one,1-methylpyridin-4(1H)-one, 1-ethylpyridin-4(1H)-one, and1-(fluoroethyl)pyridin-4(1H)-one;

(D) pyridazin-3(2H)-one, which may be substituted with 1 to 3substituents selected from C₁₋₁₀ alkyl substituted with 1 to 3 fluorineatoms, and unsubstituted C₁₋₁₀ alkyl: for example, pyridazin-3(2H)-oneand 2-methylpyridazin-3(2H)-one;

(E) pyrazin-2(1H)-one, which may be substituted with 1 to 3 substituentsselected from C₁₋₁₀ alkyl substituted with 1 to 3 fluorine atoms, andunsubstituted C₁₋₁₀ alkyl: for example, pyrazin-2(1H)-one, and1-methylpyrazin-2(1H)-one;

(F) 4H-pyran-4-one, or 2H-pyran-2-one, which may be substituted with 1to 3 substituents selected from C₁₋₁₀ alkyl substituted with 1 to 3fluorine atoms, and unsubstituted C₁₋₁₀ alkyl: for example,4H-pyran-4-one, 3-methyl-4H-pyran-4-one, 2H-pyran-2-one, and5-methyl-2H-pyran-2-one:

(G) quinolin-2(11)-one, or quinoline-1-oxide, which may be substitutedwith 1 to 3 substituents selected from C₁₋₁₀ alkyl substituted with 1 to3 fluorine atoms, and unsubstituted C₁₋₁₀ alkyl: for example,quinolin-2(1H)-one, 6-methylquinolin-2(1H)-one, quinoline-1-oxide, and4-methylquinoline-1-oxide;

(H) pyrimidin-4(3H)-one, or pyrimidine-2,4(4H,3H)-dione, which may besubstituted with 1 to 3 substituents selected from C₁₋₁₀ alkylsubstituted with 1 to 3 fluorine atoms, and unsubstituted C₁₋₁₀ alkyl:for example, pyrimidin-4(3H)-one, and pyrimidine-2,4(1H,3H)-dione, andthe like.

Examples of tautomer of the compound represented by the aforementionedgeneral formula (I) include tautomers for the aforementionedheterocyclic ring containing 1 to 4 heteroatoms selected from N, O and Sand at least one carbon atom as ring-constituting atoms, containing atleast one set of adjacent ring-constituting atoms bound by a doublebond, and further substituted with at least one oxo group as R², andspecifically, 2-pyridone (lactam) as R² and the corresponding2-hydroxypyridine (lactim) can be mentioned as such an example.

As for the compound represented by the aforementioned general formula(I), a tautomer or stereoisomer of the compound, or a pharmaceuticallyacceptable salt thereof, or a solvate thereof, preferred examples of thepharmaceutically acceptable acid include acid addition salts, andexamples of acid addition salts include salts with an inorganic acid ororganic acid such as hydrochloride, sulfate, fumarate, oxalate,methanesulfonate, and camphorsulfonate.

As for the compound represented by the aforementioned general formula(I), a tautomer or stereoisomer of the compound, or a pharmaceuticallyacceptable salt thereof, or a solvate thereof, examples of thestereoisomer include cis- and trans-isomers, racemates, optically activecompounds, and the like.

As for the compound represented by the aforementioned general formula(I), a tautomer or stereoisomer of the compound, or a pharmaceuticallyacceptable salt thereof, or a solvate thereof, the solvate is apharmaceutically acceptable solvate of the compound of the presentinvention or a salt thereof, and includes hydrate.

The compound represented by the aforementioned general formula (I), atautomer or stereoisomer of the compound, or a pharmaceuticallyacceptable salt thereof, or a solvate thereof may be chemically modifiedinto such a prodrug that it is converted into a pharmacologically activesubstance and exhibits the pharmacological activity (being activated)after it is delivered into the inside of the body or a target site.

Examples of group for constituting such a prodrug include, for example,common protective groups of hydroxy group such as a lower acyl group anda lower alkoxycarbonyl group for the case where the group constituting aprodrug exists on hydroxy group, common protective groups of amino groupsuch as a lower acyl group and a lower alkoxycarbonyl group for the casewhere the group constituting a prodrug exists on nitrogen atom, prodruggroups introduced into a carboxylic acid moiety such aspivaloyloxymethyl (tBu-C(O)O—CH₂—) group, medoxomil group, and cilexetilgroup, and the like.

An atom contained in the compound represented by the aforementionedgeneral formula (I), a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof may bereplaced with a stable isotope such as deuterium.

Hereafter, methods for preparing the compound represented by theaforementioned general formula (I), a tautomer or stereoisomer of thecompound, or a pharmaceutically acceptable salt thereof, or a solvatethereof will be shown below.

The abbreviations used herein are as follows.

Abbreviation table Boc: Tert-butoxycarbonyl CPM: Cyclopropylmethyl DMA;N,N-Dimethylacetamide DMAP: N,N-Dimethyl-4-aminopyridine DMF:N,N-Dimethylformamide DMSO: Dimethyl sulfoxide HATU:1-[Bis(dimethylamino)methylene]-1H-1,2,3- triazolo[4,5-b]pyridinium3-oxide hexafluorophosphate HOAt: 1-Hydroxy-7-azabenzotriazole HOBT:1-Hydroxybenzotriazole Me: Methyl Ms: Mesyl Ph: Phenyl TBS:tert-Butyldimethylsilyl THF: Tetrahydrofuran TLC^(:) Thin layerchromatography Ts: Tosyl WSC^(:) 1-Ethyl-3-(3dimethylaminopropyl)carbodiimide hydrochloride

(Preparation Methods)

Compounds Provided by the Present Invention that are CompoundsRepresented by the aforementioned general formula (I) wherein R⁵,R^(6a), R^(6b), R⁷, R⁸, R⁹, and R¹⁰ are hydrogens

The following compound (I) that is a compound provided by the presentinvention can be obtained by, for example, a deprotection reaction forconverting the following compound (I-A) into the compound (I).

[In the formulas, R^(1a), R^(2a), R^(3a), and R^(4a) are arbitraryfunctional groups that can be converted into R¹, R², R³, and R⁴ in theaforementioned general formula (I), respectively, or R^(1a) itself maybe R¹, R^(2a) itself may be R², R^(3a) itself may be R³, and R^(4a)itself may be R⁴. The other symbols have the same meanings as thosedefined above.]

In the aforementioned preparation method, the aforementioned compound(I) can be prepared by performing an appropriate known generaldeprotection reaction as required to convert R¹ of the aforementionedcompound (I-A) into R¹, R^(2a) of the same into R², R^(3a) of the sameinto R³, or R^(4a) of the same into R⁴. For example, when R^(1a),R^(2a), R^(3a), or R^(4a) in the aforementioned compound (I-A) containshydroxy group protected with methyl group, the methyl group as theprotective group can be removed by (1) a method of allowing borontribromide to act on the aforementioned compound (I-A) indichloromethane, or (2) a method of heating the aforementioned compound(I-A) together with a large excess amount of pyridine hydrochloride inthe absence of solvent, and thereby, the aforementioned compound (I) canbe prepared.

When R^(1a), R^(2a), R^(3a), or Ra in the aforementioned compound (I-A)contains hydroxy group protected with tert-butyldimethylsilyl (TBS)group, the TBS group as the protective group can be removed by (3) amethod of allowing ammonia dissolved in an appropriate solvent to act onthe aforementioned compound (I-A), (4) a method of allowing hydrogenchloride dissolved in an appropriate solvent to act on theaforementioned compound (I-A), or (5) a method of allowingtetrabutylammonium fluoride to act on the aforementioned compound (I-A)in THF, or the like, and thereby, the aforementioned compound (I) can beprepared.

When R^(1a), R^(2a), R^(3a), or RU contains a functional group protectedwith another protective group, the aforementioned compound (1) can beprepared from the aforementioned compound (I-A) under the generaldeprotection conditions such as those explained in Peter G. M. Wuts,“Green's Protective Groups in Organic Synthesis (6th edition, A JohnWiley & Son's, Inc., Publication).

When R^(1a), R^(2a), R^(3a), and R⁴ have different protective groups,and they must be removed under different conditions, deprotectionreactions may be successively performed under different conditionssuitable for removing the protective groups as a multi-step deprotectionreaction to prepare the aforementioned compound (I) from theaforementioned compound (I-A).

The aforementioned compound (I-A) can be obtained by, for example,performing a general acylation reaction for the following compound (I-B)mentioned in the reaction formula shown below.

[In the formulas, R^(1a), R^(2a), R^(3a), and R^(4a) are arbitraryfunctional groups that can be converted into R¹, R², R³, and R⁴ in theaforementioned general formula (I), respectively, or R^(1a) itself maybe R¹, R^(2a) itself may be R², R^(3a) itself may be R³, and R^(4a)itself may be R⁴. L¹ represents a leaving group of a common acylatingagent. The other symbols have the same meanings as those defined above.]

In the aforementioned preparation method, the aforementioned compound(I-A) can be obtained by reacting the aforementioned compound (I-B), acarboxylic acid (R^(2a)COOH), and a condensing agent such as HATU andWSC in the presence of an additive such as HOBT and DMAP, and a basesuch as triethylamine and diisopropylethylamine, as required.

The aforementioned compound (I-A) can also be obtained by reacting theaforementioned compound (I-B), a carboxylic acid chloride (R^(2a)COCl,L¹ in the formula ═Cl) or a carboxylic anhydride (L¹ in theformula=—OC(O)R^(2a)) in the presence of a base such as triethylamine,diisopropylethylamine, and pyridine.

When R^(3a) is hydroxy group (OH), in the acylation reaction mentionedin the above reaction formula, acylation of hydroxy group of Ra alsoprogresses as a side reaction in addition to the desired amidationreaction, and a product corresponding to the aforementioned compound(I-A) wherein R^(3a)=−OC(O)R^(2a) is temporarily obtained as aby-product in the reaction system. However, by treating the reactionsolution with a 2 N ammonia solution in methanol or the like, such acompound is converted again into a compound where R^(3a)═OH in apost-treatment process, and the aforementioned compound (I-A) resultingfrom selective amidation of the secondary amine in the aforementionedcompound (I-B) can be obtained as a result.

In addition, the aforementioned compound (I-A) can also be synthesizedfrom the aforementioned compound (I-B) and a corresponding carboxylicacid (R^(2a)—COOH) according to the condensation reaction explained inChristian A. G. N. Montalbetti, et al, Tetrahedron, 61(46), 2005,10827-10852.

A desired compound (I-A) can be obtained by using, for example, thecompounds described in WO2018/03583 such as compound 8 (Example 4,R^(1a)═CPM, X═O, R^(3a)═OMe, R^(4a)═H), compound 33 (Example 29, R^(1a)═Me, X═O, R^(3a) ═OMe, R^(4a)═H), compound 67 (Example 60, R^(1a)=CPM,X═CH₂, R^(3a)═H, R^(4a)═OH), compound 77 (Example 67, R^(1a)═CPM, X═CH₂,R_(3a)═OMe, R^(4a)═H), compound 116 (Example 101, R^(1a)=CPM, X═CH₂,R^(3a)═H, R^(4a)═OH), compound 130 (Example 106, R^(1a)=PhCF₂CH₂, X═CH₂,R^(3a)═OMe, R^(4a)═H), compound 185 (Example 143, R^(1a)=TBSOCH₂CH₂,X═CH₂, R^(3a)═OMe, R^(4a)═H), compound 189 (Example 144,R^(1a)═(R)—MeCH(OH)CH₂, X═CH₂, R_(3a)═OMe, R^(4a)═H), compound 350(Example 261, R^(1a)═(S)—MeCH(OH)CH₂, X═CH₂, R^(3a)═OMe, R^(4a)═H),compound 291 (Example 224, R^(1a)=CPM, X═CH₂, R^(3a)═H, R^(4a)═OMe), andcompound 297 (Example 228, R^(1a)=CPM, X═CH₂, R^(3a)═H, R^(4a)═H), andthe compounds described in WO2014/136305 such as compound 29 (Example27, R^(1a)═BocNHCH₂CH₂, X═CH₂, R^(3a)=OTBS, R^(4a)═H), and compound 68(Example 34, R^(1a)=Boc, X═CH₂, R^(3a)═OMe, R^(4a)═H) as theaforementioned compound (I-B), or by a combination of a known conversionof functional group and deprotection reaction performed by a methoddescribed in the aforementioned patent documents.

The following compound (I-A) can also be obtained by, for example, acommon alkylation reaction of the following compound (I-C) mentioned inthe reaction formula shown below.

[In the formulas, R^(1a), R^(2a), R^(3a), and R^(4a) are arbitraryfunctional groups that can be converted into R¹, R², R³, and R⁴ in theaforementioned general formula (I), respectively, or R^(1a) itself maybe R¹, R^(2a) itself may be R², R^(3a) itself may be R³, and R^(4a)itself may be R⁴. L² represents a leaving group for a common alkylatingreaction, R^(1′a) represents such a substituent that R_(1′a)—CH₂═R^(1a)is satisfied, and the other symbols have the same meanings as thosedefined above.]

In the aforementioned preparation method, the aforementioned compound(I-A) can be synthesised by allowing a corresponding aldehyde(R^(1′a)—CHO, R_(1′a) represents such a substituent thatR^(1′a)—CH₂═R^(1a) is satisfied), and a reducing agent such as sodiumtriacetoxyborohydride or sodium cyanoborohydride to act on theaforementioned compound (I-C) in an appropriate solvent in the presenceof an additive such as acetic acid as required.

The aforementioned compound T-A) can also be synthesized by allowing acorresponding alkylating agent (R^(1a)-L₂, L² represents an appropriateleaving group, for example, halogen such as Cl, Br, and I, OMs, or OTs)to act on the aforementioned compound (I-C) in a polar solvent such asDMF or an alcohol in the presence of a base such as potassium carbonate.

In addition, the method for introducing the R^(1a) group into theaforementioned compound (I-C) is not limited to the reactions describedabove, and by using a known general alkyl group introduction reactionfor amino group, which may be a multi-step reaction, the aforementionedcompound (I-A) can be prepared from the aforementioned compound (I-C).

The aforementioned compound (I-C) can be synthesized by a combination ofknown functional group conversion and deprotection reaction of anappropriate starting material described in any of the aforementionedreferences according to a method similar to any of the synthesis methodsof, for example, the compounds described in WO2018/03588 such ascompound 11 (Example 7, R^(2a)=Ph, X═O, R^(3a) ═OMe, R^(4a)═H), compound81(Example 71, R^(2a)=Ph, X═CH₂, R^(3a)═OMe, R^(4a)═H), compound 121(Example 104, R^(2a)=Ph, X═CH₂, R^(3a)”=OTBS, R^(4a)═H0, compound 149(Example 120, R^(2a)=2-pyridil, X═CH₂, R^(3a)— ═OMe, R^(4a)═H), compound116 (Example 101, R^(1a)=CPM, X═CH₂, R^(3a)═OMe, R^(4a)═H), and compound217 (Example 168, R^(2a)═CF₃, X═CH₂, R^(3a)═OMe, R^(4a)═H).

The compounds represented by the aforementioned general formula C) ofthe other types as the compounds provided by the present invention canalso be prepared by a combination of any of the aforementionedpreparation methods, methods described in the examples mentioned later,and those described in Patent documents 4 to 6, Non-patent document 11,and the like.

The compound represented by the aforementioned general formula (I), atautomer or stereoisomer thereof, or a pharmaceutically acceptable saltor a solvate thereof showed superior agonistic activity and selectivityfor the opioid δ receptor in a test concerning functional activities forthe μ, δ, and κ opioid receptors (refer to Example 40, Table 6).

The compound represented by the aforementioned general formula (I), atautomer or stereoisomer thereof, or a pharmaceutically acceptable saltor a solvate thereof significantly increased the wall-less running route(open arm) staying time ratio in the mouse and rat elevated plus mazetests, and thus exhibited anxiolytic-like effects (refer to Examples 41and 42, FIGS. 1 to 6 ). The elevated plus maze tests were performedaccording to the method described in Non-patent document 6.

It was also revealed that the compound represented by the aforementionedgeneral formula (I), a tautomer or stereoisomer thereof, or apharmaceutically acceptable salt or a solvate thereof has a superiorantidepressive action in a hyperemotional reaction inhibition test usingan olfactory bulbectomized (OBI) rat (Example 44).

Therapeutic effect for Parkinson's disease of the compound representedby the aforementioned general formula (I), a tautomer or stereoisomerthereof, or a pharmaceutically acceptable salt or a solvate thereof wasalso suggested in a reserpine-induced Parkinson's disease model mouse(Example 46).

The compound represented by the aforementioned general formula (I), atautomer or stereoisomer thereof, or a pharmaceutically acceptable saltor a solvate thereof showed a tendency of dose-dependently prolongingurination interval and increasing single urination amount in a testusing a rat cerebral infarction-induced overactive bladder model, andaccordingly, pollakiuria-improving action of the test substance wassuggested (Example 46, Table 8).

Further, the compound represented by the aforementioned general formula(I), a tautomer or stereoisomer thereof, or a pharmaceuticallyacceptable salt or a solvate thereof showed only weak inhibitory actionin a hERG (human ether-a-go-go-related gene) potassium channelinhibition test as described in Example 43 mentioned later. Thisindicates that the risks of the compounds represented by theaforementioned general formula (I), tautomers or stereoisomers of thecompounds, pharmaceutically acceptable salts thereof, and solvatesthereof for retarding the ventricular repolarisation and prolonging theQT interval in humans are low.

In addition, it was also revealed that the compound represented by theaforementioned general formula (I), a tautomer or stereoisomer thereofor a pharmaceutically acceptable salt or a solvate thereof has centralmigration sufficient for exhibiting efficacy, and high stability in ametabolic stability test using human hepatic microsomes, and it wasrevealed that they are orally administerable compounds having anxiolyticeffects, antidepressive effects, analgesic effects, anti-Parkinsoneffects, and pollakiuria and urinary incontinence-improving effects. Asfor evaluation of metabolic stability using human hepatic microsomes,the metabolic stability can be evaluated by adding a known amount of atest compound to human hepatic microsomes, incubating them for a certainperiod of time, and then quantifying the amount of the compound using LC(liquid chromatography) or the like (Example 47, Table 9).

Therefore, in consideration of the descriptions of Patent documents 1 to6, Non-patent document 1 to 10 mentioned above, and the like, thecompounds represented by aforementioned general formula (I), tautomersor stereoisomers of the compounds, pharmaceutically acceptable saltsthereof, and solvates thereof can be used for the treatment and theprevention of depression or anxiety, and can be used as prophylactic andtherapeutic agents for psychiatric disorders included in the depressiondisorder group, anxiety disorder group, bipolar disorder group,obsessive-compulsive disorder and related disorder group, psychic traumaand stress factor-related disorder group, and the like described inDSM-5 (Diagnostic and Statistical Manual of Mental Disorders, 5thedition, American Psychiatric Association) (antidepressants, anxiolyticdrugs, etc.), and as prophylactic and therapeutic agents forneurodegenerative diseases such as urinary incontinence, myocardialischemia, brain ischemia, chronic coughing, hypertension, Parkinson'sdisease, and epilepsy.

As described in IOVS, March 2013, Vol.64, No. 3; J. Neurochem. (2009)108, 741-754, and the like, application of opioid δ agonists to glaucomahas also be proposed. Therefore, the compounds represented by theaforementioned general formula (I), tautomers or stereoisomers of thecompounds, pharmaceutically acceptable salts thereof, and solvatesthereof can be used as prophylactic or therapeutic agents for glaucoma.

As used herein, depression may be a state that there is observed acombination of a mood disorder such as depressive feeling, sad feeling,and lonely feeling, decrease in activity volition, congestion of ideas,pessimistic idea, and an autonomic nerve disorder such as sleep disorderand decrease in appetite. As used herein, anxiety may be a state offeeling danger or fear with restlessness, strain, tachycardia, breathingdifficulty, and the like, although the state is not connected with astimulus that can be clearly confirmed. The depression and anxietyinclude the depressive and anxiety symptoms observed in the psychiatricdisorders described in DSM-5 mentioned above (for example, depressivesymptoms observed in bipolar disorders, and depressive and anxioussymptoms observed in PTSD), depressive state of which symptoms aremilder than those of the depression disorders described in DSM-6, butare maintained in a certain degree, and anxious state of which symptomsare milder than those of the anxiety disorders described in DSM-5, butare maintained in a certain degree.

Further, the compounds represented by the aforementioned general formulaI), tautomers or stereoisomers of the compounds, or pharmaceuticallyacceptable salts thereof, or solvates thereof may be used as medicamentsfor assisting the therapeutic treatment of any of the aforementioneddiseases.

The compounds represented by the aforementioned general formula (I),tautomers or stereoisomers of the compounds, pharmaceutically acceptablesalts thereof, and solvates thereof can also be used for therapies ofpains regarding diseases accompanied by an acute pain or chronic pain,or as prophylactic and therapeutic agents for pains of rheumatoidarthritis, osteoarthritis deformans, cancer pain accompanied by severepain such as osteoncus, diabetic neuropathic pain, postherpeticneuralgia, visceral pains, and the like.

The compounds represented by the aforementioned general formula (I),tautomer or stereoisomers of the compounds, pharmaceutically acceptablesalts thereof, and solvates thereof are preferably expected to beantidepressants and anxiolytic drugs.

The compounds represented by the aforementioned general formula (I),tautomers or stereoisomers of the compounds, pharmaceutically acceptablesalt, thereof, and solvates thereof can be administered to a human by anappropriate administration method such as oral administration orparenteral administration. Further, they can be used together with otheranxiolytic drugs, antidepressants, and analgesics.

As for preparation of pharmaceutical preparations thereof, they can beprepared in a dosage form of tablet, granule, powder, capsule,suspension, injection, suppository or the like by methods commonly usedin the field of pharmaceuticals.

For preparation of such pharmaceutical preparations, for example,commonly used excipients, disintegrating agents, binders, lubricants,dyes, and the like are used in the case of tablet. Examples of theexcipients include lactose, D-mannitol, crystalline cellulose, glucose,and the like. Examples of the disintegrating agents include starch,carboxymethylcellulose calcium (CMC-Ce), and the like. Examples of thelubricants include magnesium stearate, talc, and the like. Examples ofthe binders include hydroxypropylcellulose (HPC), gelatin,polyvinylpyrrolidone (PVP), and the like. For the preparation ofinjection, solvents, stabilizers, dissolving aids, suspending agents,emulsifiers, soothing agents, buffering agents, preservatives, and thelike are used.

As for the dose of the compound represented by the aforementionedgeneral formula (I), a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof as activeingredient, it is usually administered to adults at a dose of 0.1 μg to1 g/day, preferably 0.001 to 200 mg/day, in the case of injection; or ata dose of 1 μg to 10 g/day, preferably 0.01 to 2000 mg/day, in the caseof oral administration, but the dose may be decreased or increaseddepending on age, symptoms, and the like.

Hereafter, the present invention will be further explained in moredetail with reference to reference examples and examples. However, thepresent invention is not limited to these examples.

Names of the compounds mentioned in the examples and reference examplesare obtained by converting structural formulas depicted with ChemDrawver. 14, Cambridge Software into English compound names with a namingalgorithm of the same software, and translating them into Japanesenames.

The NMR data and the measured values of mass spectrometry (ESI+ or ESI−)of Examples 1 to 34 are shown in Tables 1 to 5.

EXAMPLES Reference Example 1-1 Synthesis of(1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol

To 300-mL round bottom flask,(1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-methoxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole(372 mg, 1.02 mmol) synthesized according to the method ofWO2013/035833, Example 67 was added, and dissolved in dichloromethane (5mL), the solution was vigorously stirred at 0° C. for 20 minutes, then a1.0 M solution of boron tribromide in dichloromethane (5 mL, 5 mmol) wasadded to the solution, and the resulting mixture was stirred at roomtemperature for 30 minutes. To the reaction solution, methanol (10 mL)was added at 0° C., and the resulting mixture was stirred at the sametemperature for 1 hour.

The reaction solution was concentrated under reduced pressure, and theresidue was suspended in chloroform (60 mL), and washed with 6% aqueousammonia (20 mL). The aqueous layer was extracted twice with chloroform(30 mL), the combined organic layers were dried over anhydrous sodiumsulfate, the insoluble matter was separated by filtration, and then thefiltrate was concentrated under reduced pressure to obtain the titlecompound (356 mg, 100%) as brown foam.

[Alternative Method]

To 500-mL round bottom flask,(1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-methoxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole(3.58 g, 9.82 mmol) synthesized according to the method ofWO2013/035833, Example 67, and pyridine hydrochloride (87 g, 753 mmol)were added, and the mixture was stirred at 200° C. for 1 hour. After thereaction, the reaction mixture was returned to room temperature,saturated aqueous potassium carbonate was added to the produced solid todissolve it, the solution was extracted with ethyl acetate andchloroform, and the combined organic layers were dried over anhydroussodium sulfate. The insoluble matter was separated by filtration, andthen the filtrate was concentrated under reduced pressure to obtain thetitle compound (3.30 g, 96%) as brown foam.

¹H NMR (CDCl₃, 400 MHz): δ 6.94 (d, 1H, J=8.2 Hz), 6.70 (dd, 1H, J=8.2,2.8 HS), 6.50 (d, 1H, J=2.3 Hz), 3.73-3.76 (m, 1H), 3.23-3.31 (m, 2H),3.05-3.12 (m, 2H), 2.77-2.99 (m, 4H), 2.56 (dd, 1H, J=11.0, 6.0 Hz),2.31 (d, 1H, J=6.4 Hz), 1.91-2.11 (m, 2H), 1.69-1.74 (m, 1H), 1.20-1.45(m, 3H), 0.93-1.10 (m, 3H), 0.77-0.83 (m, 1H), 0.42-0.51 (m, 2H),0.05-0.14 (m, 2H)

Reference Example 1-2 Synthesis of(1S,3aR,5aS,6R,11bR,11cS)-10-((tert-butyidimethylsilyl)oxy)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole

To a 200-mL round bottom flask,(1S,3aR,6aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol(694 mg, 1.98 mmol) synthesized according to the method of ReferenceExample 1-1 was added, and dissolved in DMF (20 mL), imidazole (241 mg,3.54 mmol) and tert-butyldimethylchlorosilane (498 mg, 3.31 mmol) wereadded to the solution at room temperature, and the resulting mixture wasstirred at room temperature for 2 hours. Since it was confirmed that thestarting material remained in the reaction solution, imidazole (529 mg,7.77 mmol) and tert-butyldimethylchlorosilane (503 mg, 3.34 mmol) wereadded to the reaction solution, and the resulting mixture was stirred atroom temperature for 18 hours. To the reaction solution, water (150 mL)was added, and the resulting mixture was extracted with a mixed solventof ethyl acetate and hexane (1:1, 100 mL). 6% Aqueous ammonia (30 mL)was added to the aqueous layer to make it basic, and then the resultingmixture was extracted twice with a mixed solvent of ethyl acetate andhexane (1:1, 100 ml). The combined organic layers were dried overanhydrous magnesium sulfate, then the insoluble matter was separated byfiltration, and the filtrate was concentrated under reduced pressure.The residue was purified by column chromatography (silica gel, 25 g)using methanol/chloroform (concentration gradient, 0 to 50%) and thenmethanol containing 10% concentrated aqueous ammonia/chloroform(concentration gradient, 20 to 50%) as the elution solvent to obtain thetitle compound (466 mg, 50%) as yellow syrup, and obtain the startingmaterial,(1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol(265 mg, 38%).

¹H NMR (CDCl₃, 400 MH): δ 6.94 (d, 1H, J=8.2 Hz), 6.65 (d, 1H, J=2.8HS), 6.59 (dd, 1H, J=8.2, 2.8 Hz), 3.49-3.53 (m, 1H), 3.33 (dd, 1H,J=8.2, 7.8 Hz), 3.08-3.18 (m, 2H), 2.77-2.96 (m, 4H), 2.71 (t, 1H, J=7.3Hz), 2.51-2.55 (m, 1H), 2.30 (d, 2H, J=6.4 Hz), 1.90-2.03 (m, 2H),1.63-1.68 (m, 1H), 1.35-1.43 (m, 1H), 0.91-1.13 (m, 14H), 0.77-0.83 (m,1H), 0.42-0.51 (m, 2H), 0.16 (s, 6H), 0.08-0.10 (m, 2H)

Example 1 Synthesis of2-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine1-oxide

To a 50-mL round bottom flask,(1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-11H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol(31 mg, 87 μmol) synthesized in Reference Example 1, 2-carboxypyridine1-oxide (32 mg, 0.23 mmol), and HATU (125 mg, 0.33 mmol) were added, andsuspended in THF (1.5 mL), then triethylamine (70 μL, 0.50 mmol) and DMA(200 μL) were added to the suspension, and the resulting mixture wasstirred for 1 hour at room temperature. To the reaction mixture, a 2 Nsolution of ammonia in methanol (2 ml) was added, and the resultingmixture was stirred at the same temperature for 1 hour. The reactionsolution was concentrated under reduced pressure, the obtained residuewas suspended in 6% aqueous ammonia, and the suspension was extractedwith ethyl acetate. The combined organic layers were washed withsaturated brine, and then dried over anhydrous magnesium sulfate, theinsoluble substance was separated by filtration, and then the filtratewas concentrated under reduced pressure. The obtained residue wassubjected to column chromatography (amino silica gel, 16 g) usingmethanol and chloroform (concentration gradient, 0 to 50%) as theelution solvent to obtain the title compound (18 mg, 44%) as whitesolid.

Example 2 Synthesis of4-((1S,3aR,6aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine1-oxide

In the same manner as that of Example 1,(1S,3aR,6aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-11H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol(36 mg, 0.10 mmol), 4-carboxypyridine 1-oxide (42 mg, 0.30 mmol,triethylamine (70 μL, 0.50 mmol), and HATU (108 mg, 0.28 mmol) werereacted. The reaction solution was directly subjected to columnchromatography (silica gel, 10 g) using methanol and ethyl acetatecontaining 5% triethylamine (concentration gradient, 10 to 60%) as theelution solvent, and thereby purified. The obtained syrup was dissolvedin methanol, then powdered by adding chloroform and tert-butyl methylether to the solution, and then collected by filtration to obtain thetitle compound (30 mg, 62%) as weakly brown solid.

Example 3 Synthesis of3-((1S,3aR,6aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one

In the same manner as that of Example 1,(1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,1c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol(39 mg, 0.11 mmol), 2-oxo-1,2-dihydropyridine-3-carboxylic acid (39 mg,0.28 mmd), triethylamine (70 μL, 0.60 mmol), and HATU (130 mg, 0.34mmol) were reacted. To the reaction solution, a 2 N solution of ammoniain methanol was added to terminate the reaction, then the reactionsolution was concentrated under reduced pressure, and the residue wasdirectly subjected to column chromatography (silica gel, 10 g) usingmethanol and ethyl acetate containing 5% triethylamine (concentrationgradient, 10 to 50%) as the elution solvent, and thereby purified. Theobtained residue was powdered from 6% aqueous ammonia to obtain thetitle compound (13 mg, 25%) as pale yellow powder.

Example 4 Synthesis of3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine1-oxide

In the same manner as that of Example 1,(1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol(34 mg, 97 μmol), 3-carboxypyridine 1-oxide (40 mg, 0.29 mmol),triethylamine (70 μL, 0.50 mmol), and HATU (125 mg, 0.33 mmol) werereacted. To the reaction solution, a 2 N solution of ammonia in methanolwas added to terminate the reaction, then the reaction solution wasconcentrated under reduced pressure, and the residue was directlysubjected to column chromatography (silica gel, 25 g) using a 0.1 Nsolution of ammonia in methanol and chloroform (concentration gradient,0 to 50%) as the solution solvent, and thereby purified. The obtainedsyrup was dissolved in methanol, then powdered by adding tert-butylmethyl ether to the solution, and then collected by filtration to obtainthe title compound (14 mg, 31%) as weakly brown amorphous substance.

Example 5 Synthesis of5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-11H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one

In the same manner as that of Example 1,(1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol(34 mg, 96 μmol), 6-oxo-1,6-dihydropyridine-3-carboxylic acid (40 mg,0.29 mmol), triethylamine (70 μL, 0.50 mmol, and HATU (132 mg, 0.35mmol) were reacted. To the reaction solution, a 2 N solution of ammoniain methanol was added to terminate the reaction, and then the reactionsolution was concentrated under reduced pressure. The residue wasdirectly subjected to column chromatography (silica gel, 10 g) using a0.1 N solution of ammonia in methanol and chloroform (concentrationgradient, 1 to 50%) as the elution solvent, and thereby purified. Inorder to eliminate impurities, the obtained compound was suspended inchloroform, and then the suspension was washed with 6% aqueous ammonia.The aqueous layer was extracted with chloroform, then the combinedorganic layers were dried over anhydrous sodium sulfate, then theinsoluble substance was separated by filtration, and the filtrate wasconcentrated under reduced pressure to obtain the title compound (14 mg,30%) as pale yellow powder.

Reference Example 2 Synthesis of1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid

This compound was synthesized by a method similar to the methoddescribed in WO2006/107254.

To a 50-mL round bottom flask, 2-oxo-1,2-dihydropyridine-3-carboxylicacid (500 mg, 3.69 mmol) was added, and suspended in methanol (5 mL) andwater (0.8 mL), then potassium hydroxide (400 mg, 7.13 mmol) was addedto the suspension, and the resulting mixture was stirred at 100° C. for15 minutes. The reaction solution was returned to room temperature,iodomethane (2.6 mL, 41.8 mmol) was added to the reaction solution, andthe resulting mixture was stirred at 100° C. for 45 minutes, and thenconcentrated under reduced pressure until the solvent volume was reducedby half. To the reaction solution, 3 N hydrochloric acid (20 mL) wasadded, and the produced solid was collected by filtration, washed withwater and acetonitrile, and then dried under reduced pressure to obtainthe title compound (64.9 mg, 12%) as white powder.

¹H NMR (CD₃OD, 400 MHz): δ 8.43 (dd, 1H, J=6.9, 2.3 Hz), 8.05 (dd, 1H,J=6.9, 2.3 Hz), 6.65 (t, 1H, J=6.9 Hz), 3.70 (s, 3H)

Example 6 Synthesis of3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one

(1S,3aR,5aS,6R,11bR,11cS)-14-(Cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol(30 mg, 86 μmol), 1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid(29 mg, 0.19 mmol) synthesized in Reference Example 2,diisopropylethylamine (75 μL, 0.43 mmol), and HIATU (72 mg, 0.19 mmol)were reacted in the same manner as that of Example 1, except thatdichloromethane was used as the solvent instead of THF and DMA. To thereaction solution, a 1.4 N solution of ammonia in methanol was added toterminate the reaction, and then the reaction solution was concentratedunder reduced pressure. The residue was suspended in saturated aqueoussodium hydrogen carbonate, then the suspension was extracted withchloroform, and the organic layer was dried over anhydrous sodiumsulfate. The insoluble substance was separated by filtration, and thenthe filtrate was concentrated under reduced pressure. The obtainedresidue was subjected to preparative TLC using a 1.4 N solution ofammonia in methanol and chloroform (concentration, 6%) as the developingsolvent to obtain the title compound (26.2 mg, 63%) as pale yellowamorphous substance.

Example 7 Synthesis of6-((1S,3aR,6aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methananaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one

In the same manner as that of Example 1.(1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol(66 mg, 0.19 mmol), 6-oxo-1,6-dihydropyridine-2-carboxylic acid (83 mg,0.69 mmol), triethylamine (150 μL, 1.10 mmol), and HATU (262 mg, 0.69mmol) were reacted. To the reaction solution, a 2 N solution of ammoniain methanol was added to terminate the reaction, and then the reactionsolution was concentrated under reduced pressure. The residue wasdirectly subjected to column chromatography (aminosilica gel, 10 g)using methanol and chloroform (concentration gradient, 0 to 30%) as theelution solvent, and thereby purified. The obtained syrup was dissolvedin methanol, and powdered by adding tert-butyl methyl ether to thesolution to obtain the title compound (83 mg, 94%) as brown solid.

Example 8 Synthesis of3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-6-methylpyridin-2(1H)-one

(1S,3aR,5aS,6R,11bR,11cS)-14-(Cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol(20 mg, 57 μmol), 6-methyl-2-oxo-1,2-dihydropyridine-8-carboxylic acid(19 mg, 0.13 mmol), diisopropylethylamine (60 μL, 0.29 mmol, and HATU(48 mg, 0.13 mmol) were reacted in the same manner as that of Example 1,except that DMF was used as the solvent instead of THF and DMA. T thereaction solution, a 1.4 N solution of ammonia in methanol was added toterminate the reaction, and then the reaction solution was concentratedunder reduced pressure. The residue was subjected to preparative TLCusing a 1.4 N solution of ammonia in methanol and chloroform(concentration, 10%) as the developing solvent, and thereby purified.Then, in order to eliminate impurities, the obtained solid was furthersuspended in saturated aqueous potassium carbonate, and then extractedwith chloroform. The organic layer was dried over anhydrous sodiumsulfate, then the inorganic matter was separated by filtration, and thefiltrate was concentrated under reduced pressure to obtain the titlecompound. The obtained compound was given as a hydrochloride saltaccording to Example 32 for use in the biological activity test.

Example 9 Synthesis of5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one

(1S,3aR,5aS,6R,11bR,11cS)-14-(Cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol(30 mg, 86 μmol), 1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid(29 mg, 0.19 mmol), diisopropylethylamine (75 μL, 0.43 mmol), and HATU(72 mg, 0.19 mmol) wore reacted in the same manner as that of Example 1,except that dichloromethane was used as the solvent instead of THE andDMA. To the reaction solution, a 1.4 N solution of ammonia in methanolwas added to terminate the reaction, and then the reaction solution wasconcentrated under reduced pressure. The residue was suspended insaturated aqueous sodium hydrogen carbonate, and then the suspension wasextracted with chloroform. The organic layer was dried over anhydroussodium sulfate, the insoluble substance was separated by filtration, andthen the filtrate was concentrated under reduced pressure. The obtainedresidue was subjected to preparative TLC using methanol and chloroform(concentration, 10%) as a developing solvent to obtain the titlecompound (31.1 mg, 75%) as white amorphous substance.

Reference Example 3 Synthesis of1-methyl-6-ox-1,6-dihydropyridine-2-carboxylic acid

To a 50-mL round bottom flask, 6-oxo-1,6-dihydropyridine-2-carboxylicacid (500 mg, 3.59 mmol) was added, and suspended in methanol (5 mL) andwater (0.8 mL), then potassium hydroxide (400 mg, 7.13 mmol) was addedto the suspension, and the resulting mixture was stirred at 100° C. for15 minutes. The reaction solution was returned to room temperature,iodomethane (2.6 mL, 41.8 mmol) was added to the reaction solution, andthe resulting mixture was stirred at 100° C. for 1 hour, and thenconcentrated under reduced pressure until the solvent volume was reducedby half. To the reaction solution, 3 N hydrochloric acid was added, andthe produced solid was collected by filtration, washed with water andacetonitrile, and then dried under reduced pressure to obtain the titlecompound (839 mg, 62%) as white powder.

¹H NMR (DMSO-d₆, 400 MHz): δ 7.46 (dd, 1, J=9.2, 6.9 Hz), 6.72 (dd, 1H,J=6.9, 1.4 Hz), 6.59 (dd, 1H, J=9.2, 1.4 Hz), 3.51 (s, 3H)

Example 10 Synthesis of6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl-1-methylpyridin-2(1H)-one

(1S,3aR,5aS,6R,11bR,11cS)-14-(Cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol(30 mg, 86 μmol), 1-methyl-6-oxo-1,6-dihydropyridine-2-carboxylic acid(29 mg, 0.19 mmol) synthesized according to the method of ReferenceExample 3, diisopropylethylamine (75 μL, 0.43 mmol), and HATU (72 mg,0.19 mmol) were reacted in the same manner as that of Example 1, exceptthat dichloromethane was used as the solvent instead of THF and DMA. Tothe reaction solution, a 1.4 N solution of ammonia in methanol was addedto terminate the reaction, and then the reaction solution wasconcentrated under reduced pressure. The residue was suspended insaturated aqueous sodium hydrogen carbonate, and then the suspension wasextracted with chloroform. The organic layer was dried over anhydroussodium sulfate, the insoluble substance was separated by filtration, andthen the filtrate was concentrated under reduced pressure. The obtainedresidue was subjected to preparative TLC using methanol and chloroform(concentration, 10%) as the developing solvent to obtain the titlecompound (82.7 mg, 79%) as white amorphous substance.

Example 11 Synthesis of4-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one

In the same manner as that of Example 1,(1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol(54 mg, 0.15 mmol), 2-methoxyisonicotinic acid (54 mg, 0.35 mmol),triethylamine (140 μL, 1.00 mmol), and HATU (195 mg, 0.51 mmol) werereacted. To the reaction solution, a 2 N solution of ammonia in methanolwas added to terminate the reaction, and then the reaction solution wasconcentrated under reduced pressure. The residue was suspended inchloroform, and then the suspension was washed with 6% aqueous ammonia.The aqueous layer was extracted with chloroform, the combined organiclayers were dried over anhydrous magnesium sulfate, then the insolublesubstance was separated by filtration, and the filtrate was concentratedunder reduced pressure. The obtained residue was subjected to columnchromatography (aminosilica gel, 16 g) using methanol containing 10%concentrated aqueous ammonia and chloroform as the elution solvent toobtain((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-1,2,3a,4,5,6,7,11c-octahydro-3H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-8-yl(2-methoxypyridin-4-yl)methanone(61 mg, 82%) as white solid.

¹H NMR (DMSO-d₆, 400 MHz): δ 8.20 (d, 0.6H, J=6.0 Hz), 8.15 (d, 0.4H,J=5.0 Hz), 6.88-6.97 (m, 2H), 6.80 (s, 0.6H), 6.74 (s, 0.4H), 6.64 (d,0.6H, J=2.8 Hz), 6.56 (dd, 0.6H), J=8.2, 2.3 Hz), 6.45-6.51 (m, 0.8H),4.06-4.16 (m, 1H), 3.92 (s, 1.81H), 3.88 (s, 1.2H), 3.64-3.69 (m,0.61H), 3.43-3.37 (m, 2H), 3.14-3.17 (m, 1H), 2.97-3.09 (m, 1H),2.82-2.91 (m,2H), 2.62-2.66 (m, 1M, 2.29-2.31 (m, 2H), 1.88-2.08 (m,2H), 1.66-1.80 (m, 1H), 1.42-1.57 (m, 1.6H), 1.02-1.23 (m, 2.4H),0.76-0.96 (m, 2H), 0.42-0.49 (m, 2H), 0.05-0.14 (m, 2H)

To a 100-mL round bottom flask,((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl-10-hydroxy-1,2,3a,4,5,6,7,11c-octahydro-3H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-3-yl)(2-methoxypyridin-4-ylmethanoneobtained above (48 mg, 98 μmol), and pyridine hydrochloride (2.88 g, 25mmol) were added, and the resulting mixture was stirred at 200° C. for10 minutes with heating. The reaction solution was cooled to roomtemperature, and then suspended in 6% aqueous ammonia, and thesuspension was extracted with ethyl acetate. The combined organic layerswere dried over anhydrous magnesium sulfate, then the insolublesubstance was separated by filtration, and the filtrate was concentratedunder reduced pressure. The residue was subjected to columnchromatography (aminosilica gel, 8 g) using methanol and chloroform(concentration gradient, 0 to 30%) as the elution solvent to obtain thetitle compound (35 mg, 75%) as white solid.

Example 12 Synthesis of 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methananaphtho[1,2-e]indole-3-carbonyl)pyrimidine-2,4(1H,8H)-dione

In the same manner as that of Example 1,(1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol(32 mg, 90 μmol), 2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid monohydrate (35 mg, 0.20 mmol), triethylamine (70 μL, 0.50 mmol),and HATU (114 mg, 0.30 mmol) were reacted. To the reaction solution, a 2N solution of ammonia in methanol was added to terminate the reaction,and then the reaction solution was concentrated under reduced pressure.The obtained residue was suspended in saturated aqueous sodium hydrogencarbonate, and the suspension was extracted three times with a 5:1 mixedsolution of chloroform and methanol. The combined organic layers weredried over anhydrous sodium sulfate, the insoluble substance wasseparated by filtration, and then the filtrate was concentrated underreduced pressure. The obtained residue was subjected to preparative TLCusing methanol containing 10% concentrated aqueous ammonia andchloroform (concentration, 25%) as the developing solvent to obtain thetitle compound (16 mg, 35%) as white solid.

Example 13 Synthesis of3-((1S,3aR,5aS,6R,11bR,11S)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-4(1H)-one

In the same manner as that of Example 1,(1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol(32 mg, 90 μmol), 4-oxo-1,4-dihydropyridine-3-carboxylic acid (28 mg,0.20 mmol, triethylamine (70 μL, 0.50 mmol), and HATU (114 mg, 0.30mmol) were reacted. To the reaction solution, a 2 N solution of ammoniain methanol was added to terminate the reaction, then the reactionsolution was suspended in saturated aqueous sodium hydrogen carbonate,and the suspension was extracted three times with ethyl acetate. Thecombined organic layer was dried over anhydrous sodium sulfate, theinsoluble substance was separated by filtration, and then the filtratewas concentrated under reduced pressure. The obtained residue wassubjected to preparative TLC using methanol containing 10% concentratedaqueous ammonia and chloroform (concentration, 15%) as the developingsolvent to obtain the title compound (19 mg, 44%) as white solid.

Example 14 Synthesis of2-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-4(1H)-one

In the same manner as that of Example 1,(1S,3aR,5a,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol(32 mg, 90 μmol), 4-oxo-1,4-dihydropyridine-2-carboxylic acid (28 mg,0.20 mmol), triethylamine (70 μL, 0.50 mmol), and HATU (114 mg, 0.30mmol) were reacted. To the reaction solution, a 2 N solution of ammoniain methanol was added to terminate the reaction, then the reactionsolution was suspended in saturated aqueous sodium hydrogen carbonate,and the suspension was extracted three times with a 5:1 mixed solutionof chloroform and methanol. The combined organic layer was dried overanhydrous sodium sulfate, the insoluble substance was separated byfiltration, and then the filtrate was concentrated under reducedpressure. The obtained residue was subjected to preparative TLC usingmethanol containing 10% concentrated aqueous ammonia and chloroform(concentration, 15%) as the developing solvent to obtain the titlecompound (8 mg, 20%) as white solid.

Example 15 Synthesis of4-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl-1-methylpyridin-2(1H)-one

In the same manner as that of Example 1,(1S,3aR,6aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol(32 mg, 90 μmol), 1-methyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid(31 mg, 0.20 mmol), triethylamine (70 μL, 0.50 mmol), and HATU (114 mg,0.30 mmol) were reacted, 7b the reaction solution, a 2 N solution ofammonia in methanol was added to terminate the reaction, then thereaction solution was suspended in saturated aqueous sodium hydrogencarbonate, and the suspension was extracted three times with chloroform.The combined organic layers were dried over anhydrous sodium sulfate,the insoluble substance was separated by filtration, and then thefiltrate was concentrated under reduced pressure. The obtained residuewas subjected to preparative TLC using methanol and chloroform(concentration, 5%) as the developing solvent to obtain the titlecompound (41 mg, 94%) as white solid.

Example 16 Synthesis of6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridazin-3(2H)-one

In the same manner as that of Example 1,(1S,3aR,6aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol(30 mg, 85.9 μmol), 6-oxo-1,6-dihydropyridazine-3-carboxylic acid (31mg, 0.22 mmol), triethylamine (70 μL, 0.50 mmol), and HATU (129 mg, 0.34mmol) were reacted. To the reaction solution, a 2 N solution of ammoniain methanol was added to terminate the reaction, and then the reactionsolution was concentrated under reduced pressure. The residue wassuspended in 6% aqueous ammonia, then the suspension was extracted withethyl acetate, and the organic layer was dried over anhydrous magnesiumsulfate. The insoluble substance was separated by filtration, and thenthe filtrate was concentrated under reduced pressure. The obtainedresidue was subjected to column chromatography (aminosilica gel, 16 g)using methanol and chloroform (concentration gradient, 0 to 30%) as theelution solvent to obtain the title compound (27 mg, 66%) as whitesolid.

Example 17 Synthesis of4-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)quinolin-2(1H)-one

In the same manner as that of Example 1,(1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-11H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol(33 mg, 96 μmol), 2-oxo-1,2-dihydroquinoline-4-carboxylic acid (50 mg,0.26 mmol), triethylamine (70 μL, 0.60 mmol), and HATU (128 mg, 0.34mmol) were reacted. To the reaction solution, a 2 N solution of ammoniain methanol was added to terminate the reaction, and then the reactionsolution was concentrated under reduced pressure. The residue wassuspended in 6% aqueous ammonia, then the suspension was extracted withethyl acetate, and the organic layer was dried over anhydrous magnesiumsulfate. The insoluble substance was separated by filtration, and thenthe filtrate was concentrated under reduced pressure. The obtainedresidue was subjected to column chromatography (aminosilica gel, 16 g)using methanol and chloroform (concentration gradient, 0 to 30%) as theelution solvent to obtain the title compound (28 mg, 66%) as whitesolid.

Example 18 Synthesis of6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-2H-pyran-2-one

(1S,3aR,5aS,6R,11bR,11cS)-14-(Cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol(20 mg, 57 μmol), 2-oxo-2H-pyran-5-carboxylic acid (18 mg, 0.13 mmol),diisopropylethylamine (50 μL, 0.29 mmol, and HATU (48 mg, 0.13 mmol)were reacted in the same manner as that of Example 1, except thatdichloromethane was used as the solvent instead of THF and DMA. One hourafter the start of the reaction, 1 N hydrochloric acid was added to thereaction solution, and the resulting mixture was further stirred. To thereaction solution, aqueous potassium carbonate was added to terminatethe reaction, and then the reaction solution was extracted withchloroform. The organic layer was dried over sodium sulfate, theinsoluble substance was separated by filtration, and then the filtratewas concentrated under reduced pressure. The obtained residue wassubjected to preparative TLC using methanol and chloroform(concentration, 5%) as the developing solvent to obtain the titlecompound (4.0 mg, 15%) as brown amorphous substance.

Example 19 Synthesis of2-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-4H-pyran-4-one

(1S,3aR,5aS,6R,11bR,11cS)-14-(Cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol(20 mg, 57 μmol), 4-oxo-4H-pyran-2-carboxylic acid (18 mg, 0.13 mmol),diisopropylethylamine (50 μL, 0.29 mmol), and HATU (48 mg, 0.13 mmol)were reacted in the same manner as that of Example 1, except thatdichloromethane was used as the solvent instead of THF and DMA. To thereaction solution, a 2 N solution of methylamine in methanol (0.3 mL,0.6 mmol) was added to terminate the reaction, and then the reactionsolution was concentrated under reduced pressure. The residue wassuspended in saturated aqueous sodium hydrogen carbonate, and then thesuspension was extracted with chloroform. The organic layer was driedover anhydrous sodium sulfate, the insoluble substance was separated byfiltration, and then the filtrate was concentrated under reducedpressure. The obtained residue was subjected to preparative TLC usingmethanol and chloroform (concentration, 10%) as the developing solventto obtain the title compound (4.4 mg, 16%) as brown amorphous substance.

Example 20 Synthesis of2-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-4(1H)-one

(1S,3aR,5aS,6R,11bR,11cS)-14-(Cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol(20 mg, 57 μmol), 4-oxo-4H-pyran-2-carboxylic acid (18 mg, 0.13 mmol),diisopropylethylamine (50 μL 0.29 mmol), and HATU (48 mg, 0.13 mmol)were reacted in the same manner as that of Example 1, except thatdichloromethane was used as the solvent instead of THF and DMA. To thereaction solution, a 2 N solution of methylamine in methanol (3.0 mL,6.0 mmol) was added to terminate the reaction, and then the reactionsolution was concentrated under reduced pressure. The residue wassuspended in saturated aqueous potassium carbonate, and then thesuspension was extracted with chloroform. The organic layer was driedover anhydrous sodium sulfate, the insoluble substance was separated byfiltration, and then the filtrate was concentrated under reducedpressure. The obtained residue was subjected to column chromatography(aminosilica gel, 8 g) using methanol and chloroform (concentrationgradient, 0 to 10%) as the elution solvent to obtain the title compound(19 mg, 68%) as weakly brown amorphous substance.

Example 21 Synthesis of5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyrazin-2(1H)-one

(1S,3aR,5aS,6R,11bR,11cS)-14-(Cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol(20 mg, 57 μmol), 5-oxo-4,5-dihydropyrazine-2-carboxylic acid (18 mg,0.13 mmol), diisopropylethylamine (50 μL, 0.29 mmol), and HATU (48 mg,0.13 mmol) were reacted in the same manner as that of Example 1, exceptthat dichloromethane was used as the solvent instead of THF and DMA. Tothe reaction solution, a 1.4 N solution of ammonia in methanol was addedto terminate the reaction, and then the reaction solution wasconcentrated under reduced pressure. The residue was suspended inaqueous potassium carbonate, and then the suspension was extracted withchloroform. The organic layer was dried over anhydrous sodium sulfate,the insoluble substance was separated by filtration, and then thefiltrate was concentrated under reduced pressure. The obtained residuewas subjected to column chromatography (silica gel, 10 g) using methanoland chloroform (concentration gradient, 5 to 30%) as the elution solventto obtain the title compound (12.2 mg, 45%) as weakly brown amorphoussubstance.

Example 22 Synthesis of2-((1S,3aR,5aS,6R,11bR,11cS)-10-acetoxy-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine1-oxide

To a 10-mL test tube,2-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine1-oxide (52 mg, 0.11 mmol) synthesized in Example 1 was added, andsuspended in THF (1 mL), then triethylamine (45 μL, 0.32 mmol) andacetyl chloride (15 μL, 0.21 mmol) were added to the suspension, and theresulting mixture was stirred at room temperature for 1 hour. Since itwas confirmed that the starting material remained in the reactionsolution, triethylamine (45 μL, 0.32 mmol) and acetyl chloride (15 μL,0.21 mmol) were added again, and the resulting mixture was stirred atroom temperature for 1 hour. To the reaction solution, saturated aqueoussodium hydrogen carbonate and ethyl acetate were added, the resultingmixture was vigorously stirred for 20 minutes, and then the aqueouslayer was separated, and extracted with ethyl acetate. The combinedorganic layer was dried over anhydrous magnesium sulfate, then theinsoluble substance was separated by filtration, and the filtrate wasconcentrated under reduced pressure to obtain the title compound (51 mg,89%) as yellow amorphous substance.

Example 23 Synthesis of6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one

In the same manner as that of Example 1,(1S,3aR,5aS,6R,11bR,11cS)-14-(Cyclopropylmethyl-2,3,3a,4,5,6,7,11c-octahydro1H-6,11b-(epiminoethano) 1,5a-methanonaphtho[1,2-e]indole (27 mg, 79μmol) prepared according the method described in WO2013/036833 for thecompound 297 (Example 228), 6-oxo-1,6-dihydropyridine-2-carboxylic acid(18 mg, 0.16 mmol), triethylamine (80 μL, 0.386 mmol, and HATU (70 mg,0.18 mmol) were reacted. To the reaction solution, a 2 N solution ofammonia in methanol was added to terminate the reaction, and then thereaction solution was concentrated under reduced pressure. The residuewas suspended in 6% aqueous ammonia, then the suspension was extractedwith ethyl acetate, and the organic layer was dried over anhydrousmagnesium sulfate. The insoluble substance was separated by filtration,and then the filtrate was concentrated under reduced pressure. Theobtained residue was subjected to column chromatography (aminosilicagel, 8 g) using methanol and chloroform (concentration gradient, 0 to20%) as the elution solvent. The obtained compound was dissolved inmethanol, and powdered by adding tert-butyl methyl ether to the solutionto obtain the title compound (24 mg, 67%) as white solid.

Reference Example 4 Synthesis of 8-oxo-3,4-dihydropyrazine-2-carboxylicacid

This compound was synthesized by the method described in WO2009/033084,and ¹H NMR spectrum thereof coincided to the data described in Syn.Commun., 2010, 40(20), 2988-2999.

To a 50-mL round bottom flask, 3-aminopyrazine-2-carboxylic acid (300mg, 2.17 mmol) and concentrated sulfuric acid (1.3 mL) were added. Tothe resulting mixture on an ice bath, sodium nitrite (149 mg, 2.16 mmol)dissolved in concentrated sulfuric acid (1.6 mL) was added dropwise, andthen the resulting mixture was stirred for 1 hour. The reaction solutionwas added to ice water, the resulting mixture was vigorously stirred,and the produced solid was collected by filtration. The obtained solidwas dried under reduced pressure at 60° C. for 1 hour to obtain thetitle compound (166 mg, 65%) as pale yellow crystals.

¹H NMR (DMSO-d₆, 400 MHz): δ 7.80 (d, 1H, J=3.7 Hz), 7.64 (d, 1H, J=3.7Hz)

Example 24 Synthesis of3-((1S,3aR,6aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyrazin-2(1H)-one

(1S,3aR,5aS,6R,11bR,11cS)-14-(Cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol(20 mg, 57 μmol), and 3-oxo-3,4-dihydropyrazine-2-carboxylic acid (20mg, 0.14 mmol) synthesized in Reference Example 4 were reacted in thesame manner as that of Example 1, except that HOAt (17 mg, 0.13 mmol)was used instead of triethylamine, WSC (24 mg, 0.13 mmol) was usedinstead of HATU, and as the solvent, DMF was used instead of THF. To thereaction solution, a 1.4 N solution of ammonia in methanol was added toterminate the reaction, then the reaction solution was extracted withchloroform, and the organic layer was washed with saturated aqueousammonium chloride, and then with saturated aqueous sodium hydrogencarbonate. The organic layer was dried over anhydrous sodium sulfate,the insoluble substance was separated by filtration, and then thefiltrate was concentrated under reduced pressure. The obtained residuewas subjected to preparative TLC using methanol and chloroform(concentration, 20%) as the developing solvent to obtain the titlecompound (5.9 mg, 22%) as pale yellow amorphous substance.

Example 25 Synthesis of6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyrimidine-2,4(1H,3H)-dione

(1S,3aR,5aS,6R,11bR,11cS)-14-(Cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol(20 mg, 57 μmol), and2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxylic acid (20 mg, 0.13mmol) were reacted in the same manner as that of Example 1, except thatHOAt (17 mg, 0.13 mmol) was used instead of triethylamine. WSC (24 mg,0.13 mmol) was used instead of HATU, and as the solvent, DMF was usedinstead of THF. To the reaction solution, a 1.4 N solution of ammonia inmethanol was added to terminate the reaction, and then the reactionsolution was concentrated under reduced pressure. The obtained residuewas subjected to column chromatography (silica gel, 10 g) using methanoland chloroform (concentration gradient, 5 to 30%) as the elutionsolvent. In order to eliminate impurities, the obtained compound wassuspended in chloroform and aqueous ammonia, and then collected byfiltration to obtain the title compound (2.5 mg, 9%) as weakly brownamorphous substance.

Reference Example 5 Synthesis of1-ethyl-6-oxo-1,6-dihydropyridine-2-carboxylic acid

To a 30-mL round bottom flask, 6-oxo-1,6-dihydropyridine-2-carboxylicacid (129 mg, 926 μmol) and 1,1-diethoxy-N,N-dimethylmethaneamine (1.6mL) were added, and the resulting mixture was stirred at 100° C. for 2hours. The reaction solution was cooled to room temperature, and thenconcentrated under reduced pressure. The residue was subjected to columnchromatography (silica gel, 10 g) using methanol and chloroform(concentration gradient, 0 to 20%) as the elution solvent to obtainethyl 1-ethyl-6-oxo-1,6-dihydropyridine-2-carboxylate (104 mg, 58%) ascolorless oily substance.

To a 50-mL round bottom flask, ethyl1-ethyl-6-oxo-1,6-dihydropyridine-2-carboxylate (104 mg, 533 μmol)obtained above was added, and dissolved in ethanol (3 mL), then 5 Naqueous sodium hydroxide (200 μL, 1.0 mmol) was added to the solution,and the resulting mixture was stirred at 55° C. for 2 hours. Thereaction solution was left to cool to room temperature, then made acidicwith 5 N hydrochloric acid (400 μL, 2.0 mmol), and then concentratedunder reduced pressure. Ethanol (3 mL) was added to the residue, and theresulting mixture was concentrated under reduced pressure. The residuewas suspended in ethanol (3 mL), then the insoluble substance wasseparated by filtration, and the filtrate was concentrated under reducedpressure to obtain the title compound (48 mg, 54%) as colorlesscrystalline solid.

¹H NMR (DMSO-d₆, 400 MHz): δ 7.41 (dd, 1H, J=9.2, 6.0 Hz), 6.65 (d, 1H,J=6.4 Hz), 6.53 (d, 1H, J=8.7 Hz), 4.06 (q, 2H, J=6.9 Hz), 1.17 (t, 3H,J=6.9 Hz)

Example 26 Synthesis of6-((1S,3aR,6aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-ethylpyridin-2(1H)-one

In the same manner as that of Example 1,(1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)1,5a-methanonaphtho[1,2-e]indol-10-ol(32 mg, 92 μmol), 1-ethyl-6-oxo-1,6-dihydropyridine-2-carboxylic acid(38 mg, 0.19 mmol) synthesized in Reference Example 6, triethylamine (70μL, 0.50 mmol), and HATU (136 mg, 0.36 mmol) were reacted. To thereaction solution, a 2 N solution of ammonia in methanol was added toterminate the reaction, and then the reaction solution was concentratedunder reduced pressure. The residue was suspended in 6% aqueous ammonia,then the suspension was extracted with ethyl acetate, and the organiclayer was dried over anhydrous magnesium sulfate. The insolublesubstance was separated by filtration, and then the filtrate wasconcentrated under reduced pressure. The obtained residue was subjectedto column chromatography (aminosilica gel, 8 g) using methanol andchloroform (concentration gradient, 0 to 20%) as the elution solvent.The obtained compound was dissolved in methanol, and powdered by addingtert-butyl methyl ether to the solution to obtain the title compound (35mg, 76%) as white solid.

Example 27 Synthesis of6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyrimidin-4(3H)-one

(1S,3aR,5aS,6R,11bR,11cS)-10-((tert-Butyldimethylsilyl)oxy)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole(30 mg, 65 μmol), and 6-oxo-1,6-dihydropyrimidine-4-carboxylic acid (20mg, 0.14 mmol) were reacted in the same manner as that of Example 1,except that HOAt (19 mg, 0.14 mmol) was used instead of triethylamine,WSC (27 mg, 0.14 mmol) was used instead of HATU, and as the solvent, DMFwas used instead of THF. The residue was suspended in water, and thenthe suspension was extracted with ethyl acetate. The organic layer wasdried over anhydrous sodium sulfate, the insoluble substance wasseparated by filtration, and then the filtrate was concentrated underreduced pressure. The obtained residue was subjected to columnchromatography (silica gel, 10 g) using methanol and chloroform(concentration gradient, 0 to 10%) as the elution solvent.

To a 100-mL round bottom flask, the solid obtained above, methanol (2mL), and aqueous ammonia were added, and the resulting mixture wasstirred at room temperature for 8 days. The reaction solution wasconcentrated, and then the residue was suspended in chloroform. Then,the insoluble substance was separated by filtration, and the filtratewas concentrated under reduced pressure. The obtained residue wassubjected to preparative TLC using methanol and chloroform(concentration, 20%) as the developing solvent to obtain the titlecompound (1.7 mg, 6%) as white amorphous substance.

Reference Example 6 Synthesis of1-ethyl-6-oxo-1,6-dihydropyridine-8-carboxylic acid

To 2-oxo-2H-pyran-5-carboxylic acid (200 mg, 1.43 mmol) and DMAP (17.5mg, 143 μmol) dissolved in dichloromethane (3.8 mL) and THF (3.3 mL),WSC (274 mg, 1.43 mmol) and benzyl alcohol (148 μL, 1.43 mmol) wereadded, and the resulting mixture was stirred at room temperature for 2hours. To the reaction solution, water was added, the insolublesubstance was separated by filtration, and then the reaction solutionwas extracted with hexane. The organic layer was washed with saturatedaqueous sodium hydrogen carbonate. The combined organic layer was driedover anhydrous sodium sulfate, then the insoluble substance wasseparated by filtration, and the filtrate was concentrated under reducedpressure. The obtained residue was dissolved in methanol (10 mL)together with ethylamine hydrochloride (112 mg, 1.37 mmol), andtriethylamine (520 μL, 3.73 mmol) was added to the solution, followed bystirring the resulting mixture at room temperature for 16 hours. Afterthe reaction, the reaction mixture was concentrated under reducedpressure, and saturated aqueous sodium hydrogen carbonate was added tothe obtained residue. The resulting mixture was extracted withchloroform, and the organic layer was washed with saturated brine. Thecombined organic layers were dried over anhydrous sodium sulfate, thenthe insoluble substance was separated by filtration, and the filtratewas concentrated under reduced pressure. The residue was subjected tosilica gel column chromatography (10 g) using ethyl acetate and hexane(concentration gradient, 10 to 60%) as the elution solvent to obtainbenzyl 1-ethyl-6-oxo-1,6-dihydropyridine-3-carboxylate (126 mg, 34% for2 steps) as pale yellow amorphous substance.

Benzyl 1-ethyl-6-oxo-1,6-dihydropyridine-3-carboxylate obtained abovewas dissolved in methanol (2 mL) and ethyl acetate (2 ml), and 10%palladium/carbon was added to the solution, followed by stirring theresulting mixture at room temperature for 2 hours under a hydrogenatmosphere. After the reaction, the insoluble substance was removed byfiltration through Celite, and the obtained solution was concentrated toobtain the title compound (73 mg, 89%) as pale yellow amorphoussubstance.

¹H NMR (CH₃OD, 400 MHz): δ 8.43 (d, 1H, J=2.3 Hz), 7.95 (dd, 1H, J=9.6,2.3 Hz), 6.51 (d, 1H. J=9.6 Hz), 4.07 (q, 2H. J=7.3 Hz), 1.34 (t, 3H,J=7.3 Hz)

Example 28 Synthesis of5-((1S,3aR,5aS,6R,11bR,11cS)-4-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-ethylpyridin-2(1H)-one

(1S,3aR,5aS,6R,11bR,11cS)-14-(Cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol(15 mg, 43 μmol), 1-ethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid(16 mg, 94 μmol) synthesized in Reference Example 6,diisopropylethylamine (37 μL, 0.21 mmol), and HATU (36 mg, 94 μmol) werereacted in the same manner as that of Example 1, except that THF alonewas used as the solvent. To the reaction solution, a 1.4 N solution ofammonia in methanol was added to terminate the reaction, and then thereaction solution was concentrated under reduced pressure. The residuewas suspended in saturated aqueous sodium hydrogen carbonate, and thenthe suspension was extracted with chloroform. The organic layer wasdried over anhydrous sodium sulfate, the insoluble substance wasseparated by filtration, and then the filtrate was concentrated underreduced pressure. The obtained residue was subjected to columnchromatography (silica gel, 10 g) using methanol and chloroform(concentration gradient, 0 to 30%) as the elution solvent to obtain thetitle compound (13.3 mg, 62%) as white amorphous substance.

Example 29 Synthesis of2-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine1-oxide hydrochloride

To a 50-mL round bottom flask,2-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine1-oxide (79 mg, 0.17 mmol) synthesized in Example 1 was added, anddissolved in ethanol (2 mL), then 2 N hydrochloric acid (1 mL) was addedto the solution, and the obtained solution was concentrated underreduced pressure. The obtained residue was dried at 80° C. for 18 hoursunder reduced pressure to obtain the title compound (85 mg, 99%) aswhite amorphous substance.

Example 30 Synthesis of3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-onehydrochloride

To a 50-mL round bottom flask,3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one(44 mg, 93 μmol) synthesized in Example 3 was added, and dissolved in 2N hydrochloric acid (2 mL), and the obtained solution was concentratedunder reduced pressure. The obtained residue was dried at 100° C. for 18hours under reduced pressure to obtain the title compound (40 mg, 84%)as yellow solid.

Example 31 Synthesis of3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-onehydrochloride

To a 10-mL test tube,3-((1S,3aR,6aS,6R,11bR,1cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indolo-3-carbonyl)-1-methylpyridin-2(1H)-one(26 mg, 54 μmol) synthesized in Example 6, and ethyl acetate were added.The resulting mixture was extracted with 1 N hydrochloric acid, and theaqueous layer was concentrated under reduced pressure. The obtainedresidue was dried at 60° C. for 1 hour under reduced pressure to obtainthe title compound (23 mg, 83%) as pale yellow amorphous substance.

Example 32 Synthesis of3-((1S,3aR,6aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-6-methylpyridin-2(1H)-onehydrochloride

To a 10-mL test tube,3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-6-methylpyridin-2(1H)-onesynthesized in Example 8, and ethyl acetate were added. The resultingmixture was extracted with 1 N hydrochloric acid, and the aqueous layerwas concentrated under reduced pressure. The obtained residue was driedunder reduced pressure to obtain the title compound (11 mg, 39% for 2steps from Example 8) as pale yellow amorphous substance.

Example 33 Synthesis of5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-onehydrochloride

To a 10-mL test tube,5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one(31 mg, 64 μmol) synthesized in Example 9, and ethyl acetate were added.The resulting mixture was extracted with 1 N hydrochloric acid, and theaqueous layer was concentrated under reduced pressure. The obtainedresidue was dried at 60*C for 2 hours under reduced pressure to obtainthe title compound (22 mg, 67%) as pale yellow amorphous substance.

Example 34 Synthesis of6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-onehydrochloride

To a 10-mL test tube,6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one(33 mg, 67 μmol) synthesized in Example 10, and ethyl acetate wereadded. The resulting mixture was extracted with 1 N hydrochloric acid,and the aqueous layer was concentrated under reduced pressure. Theobtained residue was dried at 60° C. for 2 hours under reduced pressureto obtain the title compound (33 mg, 94%) as weakly brown amorphoussubstance.

TABLE 1 Deuterated solvent used for NMR Example measurement NMR data M/S1 DMSO-d6 9.07 (br s, 1H), 8.21-8.27 (m, 1H), 7.29- 472.21 7.44 (m, 3H),6.80-6.89 (m, 1H), 6.37- M + H 6.56 (m, 2H), 4.33 (br s, 0.5H), 3.86 (brs, 0.5H), 2.71-3.48 (m, 9H), 2.09-2.30 (m, 2H), 1.72-1.91 (m, 2H),1.31-1.61 (m, 2H), 0.93-1.09 (m, 3H), 0.61-0.79 (m, 2H), 0.31-0.46 (m,2H), −0.03-0.07 (m, 2H) 2 CD3OD 8.36 (d, 1.4H, J = 7.3 Hz), 8.32 (d,472.19 0.6H, J = 7.3 Hz), 7.66 (d, 1.4H, J = 6.9 M + H Hz), 7.54-7.58(m, 0.6H), 6.96-7.05 (m, 1H), 6.53-6.69 (m, 2H), 4.66-4.70 (m, 0.7H),4.15-4.20 (m, 0.3H), 3.43-3.81 (m, 2H), 3.01-3.32 (m, 7H), 1.95-2.05 (m,2H), 1.77-1.86 (m, 2H), 1.55-1.67 (m, 2H), 1.43-1.50 (m, 3H), 0.88-1.00(m, 2H), 0.52-0.65 (m, 2H), 0.17-0.31 (m, 2H). 3 DMSO-d6 11.85 (br s,0.6H), 11.80 (br s, 0.4H), 472.19 9.06 (br s, 1H), 7.34-7.42 (m, 2H),6.89 M + H (d, 0.7H, J = 8.2 Hz), 6.84 (d, 0.3H, J = 7.8 Hz), 6.40-6.55(m, 2H), 6.18 (t, 0.7H, J = 6.9 Hz), 6.13 (t, 0.3H, J = 6.9 Hz),4.29-4.33 (m, 0.7H), 3.95-4.08 (m, 0.6H), 3.79-3.84 (m, 0.3H), 3.54-3.61(m, 1H), 2.63-3.44 (m, 7.4H), 2.22-2.31 (m, 1H), 2.12-2.19 (m, 1H),1.74-1.90 (m, 2H), 1.49-1.59 (m, 1H), 1.27-1.40 (m, 1.7H), 0.90-1.14 (m,2.3H), 0.69- 0.75 (m, 1H), 0.54-0.64 (m, 1H). 4 CD3OD 8.46-8.48 (m, 1H),8.37 (d, 0.7H, J = 7.3 472.18 Hz), 8.33 (d, 0.3H, J = 6.9 Hz), 7.53- M +H 7.71 (m, 2H), 6.92-7.02 (m, 1H), 6.52- 6.68 (m, 4.64-4.69 (m, 0.6H),4.11-4.19 (m, 0.6H), 3.59-3.64 (m, 1H), 3.43-3.46 (m, 0.4H), 2.92-3.39(m, 7.4H), 1.96- 2.08 (m, 2H), 1.07-1.85 (m, 7H), 0.82- 0.97 (m, 2H),0.46-0.65 (m, 2H), 0.10- 0.30 (m, 2H). 5 DMSO-d6 11.70 (br s, 1H), 9.03(br s, 1H), 7.47- 472.19 7.67 (m, 2H), 6.87-6.89 (m, 1H), 6.47- M + H6.54 (m, 2H), 6.26-6.28 (m, 1H), 3.63- 4.53 (m, 3H), 3.16 (t, 1H, J =12.8 Hz), 2.95-3.02 (m, 2.5H), 2.75-2.82 (m, 2.5H), 2.46-2.52 (m, 1H),2.28 (dd, 1H, J = 12.8, 5.5 Hz), 2.16 (dd, 1H, J = 12.8, 6.4 Hz),1.74-1.91 (m, 2H), 1.39- 1.60 (m, 2H), 1.11-1.20 (m, 2H), 0.94- 0.99 (m,1H), 0.66-0.77 (m, 2H), 0.35- 0.42 (m, 2H), −0.02-0.06 (m, 2H). 6 CDCl37.49 (dd, 0.7H, J = 6.9, 1.8 Hz), 7.46 (dd, 0.3H, J = 6.9, 1.8 Hz),7.33-7.39 (m, 1H), 6.89 (d, 0.7H, J = Hz), 6.89 (d, 0.3H, J = 8.2 Hz),6.58-6.74 (m, 2H), 6.22 (t, 0.7H, J = 6.9 Hz), 6.20 (t, 0.3H, J = 6.9Hz), 4.62-4.72 (m, 0.7H), 4.11- 4.21 (m, 0.6H), 3.67-3.80 (m, 1H), 3.59(s, 2.1H), 3.55 (s, 0.9H), 3.48-3.61 (m, 1H), 3.22-3.36 (m, 1H),2.72-3.19 (m, 5H), 2.47-2.64 (m, 0.7H), 2.21-2.42 (m, 1.7H), 1.80-2.13(m, 1.7H), 1.35-1.77 (m, 2.4H), 0.95-1.34 (m, 3.2H), 0.73- 0.94 (m, 2H),0.36-0.55 (m, 2H), 0.01- 0.19 (m, 2H). 7 CD3OD 7.61 (dd, 0.7H, J = 8.7,6.9 Hz), 7.53 472.2 (dd, 0.3H, J = 9.2, 6.9 Hz), 6.95 (d, M + H 0.7H, J= 8.2 Hz), 6.91 (d, 0.3H, J = 9.2 Hz), 6.46-6.63 (m, 4H), 4.62 (t, 0.7H,J = 6.9 Hz), 4.31 (t, 0.3H, J = 6.9 Hz), 4.08 (m, 0.3H), 3.87 (m, 0.7H),3.70 (d, 0.7H, J = 11.5 Hz), 3.59 (d, 0.3H, J = 12.4 Hz), 3.25-3.38 (m,2H), 3.08-3.18 (m, 2H), 2.84-3.01 (m, 2H), 2.56 (dd, 1H, J = 11.5, 4.6Hz), 2.28-2.34 (m, 2H), 1.89-2.09 (m, 2H), 1.67-1.48 (m, 1H), 1.40-1.57(m, 2H), 1.06-1.26 (m, 2H), 0.77-0.95 (m, 2H), 0.41-0.50 (m, 2H),0.05-0.13 (m, 2H).

TABLE 2 Deuterated solvent used for NMR Example measurement NMR data M/S8 CDCl3 12.15 (br s, 1H), 8.20 (br s, 1H), 7.54 (d, 0.5H), J = 5.0 Hz),7.53 (d, 0.5H, J = 5.0 Hz), 6.83-6.94 (m, 1H), 6.72 (d, 0.5H, J = 2.3Hz), 6.51-6.63 (m, 1.5H), 6.13 (d, 0.5H), J = 7.3 Hz), 6.07 (d, 0.5H), J= 6.9 Hz), 4.57-4.68 (m, 0.5H), 4.14-4.33 (m, 1H), 3.71-3.85 (m, 1H),3.46-3.60 (m, 0.5H), 3.20-3.34 (m, 1H), 2.66-3.17 (m, 5H), 2.45-2.60 (m,1H), 0.69-2.42 (m, 14H), 0.38-0.52 (m, 2H), 0.02-0.14 (m, 2H). 9 CDCl37.85 (s, 0.7H), 7.69 (s, 0.3H), 7.61 (d, 0.7H, J = 8.2 Hz), 7.44 (d,0.3H, J = 8.7 HZ), 6.85-6.93 (m, 1H), 6.47-6.67 (m, 3H), 4.56-4.78 (m,0.7H), 4.10-4.36 (m, 0.6H), 3.65-3.87 (m, 2H), 3.59 (s, 2.1H), 3.55 (s,0.9H), 3.25-3.45 (m, 1H), 2.67-3.21 (m, 5H), 2.48-2.65 (m, 0.7H),2.20-2.43 (m, 1.7H), 1.64-2.12 (m, 2.8H), 0.72-1.50 (m, 6.5H), 0.38-0.56(m, 2H), 0.03-0.19 (m, 2H). 10 DMSO-d6 9.09 (s, 0.7H), 9.07 (s, 0.3H),7.43 (dd, 486.21 0.7H, J = 9.2, 6.9 Hz), 7.31-7.40 (m, M + H 0.3H), 6.93(d, 0.7H), J = 8.7 Hz), 6.87 (d, 0.3H, J = 7.8 Hz), 6.20-6.61 (m, 4H),3.57-4.49 (m, 2H), 3.32 (s, 0.9H), 3.29 (s, 2.1H), 2.44-3.48 (m, 8H),2.25-2.34 (m, 1H), 2.14-2.23 (m, 1H), 1.74-1.99 (m, 2H), 1.53-1.68 (m,1H), 1.30-1.50 (m, 2H), 0.95-1.25 (m, 2H), 0.62-0.81 (m, 2H), 0.36-0.48(m, 2H), 0.06-0.10 (m, 2H). 11 DMSO-d6 11.70 (br s, 1H), 9.07 (s, 1H),7.42 (d, 472.22 0.6H, J = 6.4 Hz), 7.37 (d, 0.4H, J = 6.0 M + H Hz),6.93 (d, 0.6H, J = 8.2 Hz), 6.88 (d, 0.4H, J = 8.2 Hz), 6.45-6.58 (m,2H), 6.30 (s, 0.6H), 6.24 (s, 0.4H), 6.13 (d, 0.6H, J = 6.9 Hz), 6.08(d, 0.4H, J = 6.4 Hz), 4.39-4.43 (m, 0.6H), 4.04-4.07 (m, 0.4H),3.94-3.89 (m, 0.4H), 3.60-3.65 (m, 0.6H), 2.98-3.48 (m, 5H), 2.46-2.91(m, 3H), 2.26-2.34 (m, 1H), 2.16-2.22 (m, 1H), 1.75-1.94 (m, 2H),1.11-1.63 (m, 4H), 0.96-1.03 (m, 1H), 0.66-0.78 (m, 2H), 0.41-0.43 (m,2H), 0.03-0.10 (m, 2H). 12 CD3OD 7.64 (s, 1H), 6.96 (d, 0.8H, J = 8.7Hz), 489.19 6.93 (d, 0.2H, J = 8.3 Hz), 6.51-6.67 (m, M + H 2H),2.81-5.14 (m, 10H), 2.51-2.62 (m, 1H), 2.29-2.39 (m, 2H), 1.87-2.15 (m,2H), 1.66-1.80 (m, 0.8H), 1.38-1.60 (m, 1.2H), 1.05-1.32 (m, 3H),0.74-0.95 (m, 1H), 0.40-0.56 (m, 2H), 0.03-0.20 (m, 2H). 13 DMSO-d611.45-11.66 (m, 1H), 9.00-9.19 (m, 1H), 472.22 7.48-7.78 (m, 2H), 6.92(d, 0.7H, J = 8.7 M + H Hz), 6.87 (d, 0.3H, J = 8.3 Hz), 6.39- 6.64 (m,2H), 6.15 (d, 0.7H, J = 7.3 Hz), 6.12 (d, 0.3H, J = 6.9 Hz), 4.25-4.40(m, 0.7H), 3.97-4.09 (m, 0.3H), 2.41-3.92 (m, 9H), 2.10-2.37 (m, 2H),1.73-2.00 (m, 2H), 0.53-1.69 (m, 7H), 0.34-0.50 (m, 2H), −0.04-0.15 (m,2H). 14 DMSO-d6 10.84 (br s, 1H), 9.10 (s, 0.7H), 9.05 (s, 472.22 0.3H),8.08-8.39 (m, 1H), 6.39-7.05 (m, M + H 5H), 4.45-4.65 (m, 1H), 3.68-4.00(m, 1H), 2.44-3.61 (m, 8H), 2.12-2.37 (m, 2H), 1.74-2.01 (m, 2H),0.58-1.69 (m, 7H), 0.35-0.50 (m, 2H), 0.00-0.14 (m, 2H).

TABLE 3 Deuterated solvent used for NMR Example measurement NMR data M/S15 CDCl3 7.30-7.40 (m, 1H), 6.89-6.99 (m, 1H), 486.23 6.52-6.69 (m, 3H),6.18-6.26 (m, 1H), M + H 4.60-4.73 (m, 0.5H), 4.09-4.33 (m, 1H),3.67-3.78 (m, 0.5H), 3.49-3.61 (m, 4H), 3.26-3.44 (m, 0.5H), 2.71-3.18(m, 4.5H), 0.71-2.66 (m, 13H), 0.39-0.56 (m, 2H), 0.04-0.17 (m, 2H). 16DMSO-d6 9.07 (br s, 0.7H), 9.05 (br s, 0.3H), 7.61- 473.22 7.68 (m, 1H),6.87-6.93 (m, 2H), 6.48- M + H 6.60 (m, 2H), 4.56-4.59 (m, 0.3H), 4.48-4.52 (m, 0.7H), 4.06 (q, 0.3H, J = 5.0 Hz), 3.95-4.02 (m, 1H), 3.82-3.84(m, 0.7H), 2.50-3.52 (m, 7H), 2.27-2.33 (m, 1H), 2.17-2.22 (m, 1H),1.80-1.94 (m, 2H), 1.58-1.64 (m, 1H), 0.98-1.41 (m, 5H), 0.69-0.78 (m,1H), 0.41-0.43 (m, 2H), 0.02-0.09 (m, 2H). 17 DMSO-d6 9.11 (br s, 1H),7.50-7.59 (m, 1H), 7.30- 522.26 7.36 (m, 2H), 7.20-7.23 (m, 1H), 6.94M + H (d, 0.7H, J = 8.2 Hz), 6.83 (d, 0.3H, J = 7.3 Hz), 6.38-6.62 (m,3H), 4.50-4.57 (m, 1H), 3.40-3.62 (m, 4H), 3.14-3.24 (m, 1H), 2.74-3.03(m, 4H), 2.52-2.56 (m, 1H), 2.25-2.35 (m, 1H), 2.15-2.22 (m, 1H),1.77-1.95 (m, 2H), 1.41-1.55 (m, 2H), 0.95-1.06 (m, 2H), 0.70-0.81 (m,2H), 0.38-0.44 (m, 2H), 0.02-0.09 (m, 2H). 18 CD3OD 7.89-8.12 (m, 2H),6.99 (d, 0.2H, J = 7.8 471.22 Hz), 6.97 (d, 0.8H, J = 8.2 Hz), 6.64 (d,M + H 0.2H, J = 2.8 Hz), 6.60-6.62 (m, 1.8H), 5.61 (d, 0.8H, J = 9.6Hz), 5.57 (d, 0.2H, J = 9.2 Hz), 3.23-5.24 (m, 5H), 3.11-3.22 (m, 2H),2.85-3.00 (m, 2H), 2.54-2.63 (m, 1H), 2.27-2.40 (m, 2H), 1.93-2.21 (m,2H), 1.44-1.87 (m, 2H), 0.74-1.41 (m, 5H), 0.42-0.52 (m, 2H), 0.06-0.18(m, 2H). 19 DMSO-d6 9.10 (s, 0.7H), 9.07 (s, 0.3H), 8.20 (d, 473.250.7H, J = 6.0 Hz), 8.13 (d, 0.3H, J = 5.5 M + H Hz), 6.87-6.97 (m, 1H),6.45-6.73 (m, 3H), 6.40 (dd, 0.7H, J = 6.0, 2.3 Hz), 6.34 (dd, 0.3H, J =5.5, 2.3 Hz), 4.24- 4.51 (m, 1H), 3.87-4.01 (m, 1H), 2.38- 3.81 (m, 8H),2.14-2.35 (m, 2H), 1.73- 1.98 (m, 2H), 1.53-1.66 (m, 1H), 1.35- 1.49 (m,1H), 0.63-1.31 (m, 5H), 0.34- 0.50 (m, 2H), 0.03-0.14 (m, 2H). 20DMSO-d6 9.09 (s, 1H), 7.67 (d, 0.7H, J = 7.8 Hz), 486.28 7.63 (d, 0.3H,J = 7.3 Hz), 6.93 (d, M + H 0.7H, J = 8.2 Hz), 6.88 (d, 0.3H, J = 8.2Hz), 6.58 (d, 0.7H, J = 2.3 Hz), 6.49- 6.55 (m, 1H), 6.46 (dd, 0.3H, J =8.2, 2.3 Hz), 6.07-6.14 (m, 1.7H), 6.05 (dd, 0.3H, J = 7.8, 2.8 Hz),4.36-4.44 (m, 0.7H), 3.80-4.23 (m, 0.6H), 3.63-3.67 (m, 0.7H), 3.47 (s,2.1H), 3.44 (s, 0.9H), 2.37-3.54 (m, 8H), 2.25-2.35 (m, 1H), 2.18 (dd,1H, J = 12.4, 6.4 Hz), 1.73- 1.96 (m, 2H), 1.53-1.67 (m, 1H), 1.30- 1.51(m, 2H), 1.11-1.19 (m, 1H), 0.95- 1.08 (m, 1H), 0.61-0.81 (m, 2H), 0.35-0.48 (m, 2H), 0.01-0.11 (m, 2H). 21 DMSO-d6 9.06-9.13 (m, 1H), 7.94 (s,0.7H), 7.78- 473.25 7.91 (m, 1.3H), 6.85-6.98 (m, 1H), 6.60 M + H (s,0.7H), 6.45-6.57 (m, 1.3H), 4.85-4.95 (m, 0.3H), 4.49-4.60 (m, 0.7H),3.88- 4.07 (m, 1.7H), 2.39-3.56 (m, 7.3H), 2.15-2.35 (m, 2H), 1.77-1.99(m, 2H), 1.52-1.67 (m, 1H), 0.96-1.44 (m, 4H), 0.62-0.92 (m, 2H),0.38-0.48 (m, 2H), 0.01-0.13 (m, 2H).

TABLE 4 Deuterated solvent used for NMR Example measurement NMR data M/S22 CDCl3 8.14-8.18 (m, 1H), 7.03-7.34 (m, 4H), 514.27 6.75-6.85 (m, 2H),4.68 (m, 0.6H), 4.09- M + H 4.20 (m, 1H), 3.62-3.70 (m, 0.4H), 3.29-3.40 (m, 0.6H), 2.87-3.13 (m, 6.4H), 2.51-2.56 (m, 1H), 1.85-2.26 (m,8H), 1.58-1.67 (m, 2H), 1.10-1.24 (m, 2H), 0.67-0.89 (m, 2H), 0.36-0.46(m, 2H), 0.03-0.13 (m, 2H). 23 CDCl3 7.05-7.43 (m, 5H), 6.27-6.68 (m,2H), 456.29 4.81-4.84 (m, 0.7H), 4.50-4.53 (m, M + H 0.3H), 4.27-4.36(m, 0.3H), 4.10 (t, 0.7H, J = 11.0 Hz), 3.84 (d, 0.7H, J = 3.8 Hz),3.57-3.64 (m, 0.3H), 3.34- 3.48 (m, 1H), 2.78-3.20 (m, 5H), 2.54- 2.61(m, 1H), 2.26-2.36 (m, 2H), 1.87- 2.05 (m, 2H), 1.15-1.78 (m, 5H), 0.75-0.93 (m, 2H), 0.47 (d, 2H, J = 7.8 Hz), 0.06-0.13 (m, 2H). 24 DMSO-d69.10 (s, 0.6H), 9.07 (s, 0.4H), 7.19-7.62 473.27 (m, 2H), 6.92 (d, 0.6H,J = 8.7 Hz), 6.87 M + H (d, 0.4H, J = 9.2 Hz), 6.66-6.36 (m, 2H),4.33-4.40 (m, 0.6H), 3.91-3.99 (m, 0.4H), 3.85 (dd, 0.4H, J = 12.8, 8.7Hz), 3.59 (dd, 0.6H, J = 10.5, 8.2 Hz), 2.38- 3.52 (m, 8H), 2.14-2.34(m, 2H), 1.73- 1.96 (m, 2H), 1.51-1.70 (m, 1H), 1.29- 1.45 (m, 1H),0.93-1.27 (m, 3H), 0.49- 0.91 (m, 2H), 0.35-0.48 (m, 2H), −0.01- 0.12(m, 2H). 25 DMSO-d6 8.96-9.68 (m, 2H), 6.91 (d, 0.6H, J = 8.2 489.26Hz), 6.88 (d, 0.4H, J = 8.2 Hz, 6.58 (d, M + H 0.6H, J = 2.3 Hz),6.48-6.54 (m, 1H), 6.45 (dd, 0.4H, J = 8.2, 2.3 Hz), 4.88- 5.19 (m, 1H),4.35-4.44 (m, 0.4H), 4.28- 4.35 (m, 0.6H), 3.70-3.82 (m, 1H), 2.39- 3.61(m, 8H), 2.24-2.34 (m, 1H), 2.14- 2.23 (m, 1H), 1.73-1.99 (m, 2H), 1.48-1.66 (m, 1H), 0.92-1.45 (m, 4H), 0.56- 0.82 (m, 2H), 0.33-0.50 (m, 2H),−0.02- 0.14 (m, 2H). 26 DMSO-d6 9.06 (br s, 0.7H), 9.05 (br s, 0.3H),7.30- 500.31 7.41 (m, 1H), 6.90 (d, 0.7H, J = 8.2 Hz), M + H 6.84 (d,0.3H, J = 8.2 Hz), 6.56 (br s, 1H), 6.50 (dd, 1H, J = 8.2, 2.3 Hz),6.22-6.43 (m, 2H), 4.39 (br s, 1H), 3.52- 4.14 (m, 4H), 2.90-3.21 (m,4H), 2.70- 2.79 (m, 2H), 2.42-2.50 (m, 1H), 2.13- 2.29 (m, 2H),1.72-1.95 (m, 3H), 1.53- 1.63 (m, 1H), 1.27-1.39 (m, 1H), 0.94- 1.18 (m,5H), 0.57-0.80 (m, 2H), 0.38 (d, 2H, J = 7.8 Hz), 0.02 (br s, 2H). 27DMSO-d6 9.08 (s, 0.6H), 9.06 (s, 0.4H), 8.22 (s, 473.28 0.6H), 8.15 (s,0.4H), 6.92 (d, 0.6H, J = M + H 8.2 Hz), 6.88 (d, 0.4H, J = 7.8 Hz),6.59 (d, 0.6H, J = 2.8 Hz), 6.52 (dd, 0.6H, J = 8.2, 2.8 Hz), 6.49 (d,0.4H, J = 2.3 Hz), 6.46 (dd, 0.4H, J = 7.8, 2.3 Hz), 6.40 (s, 0.6H),6.37 (s, 0.4H), 4.30-4.46 (m, 1H), 3.68-3.93 (m, 1H), 2.40-3.65 (m, 8H),2.14-2.34 (m, 2H), 1.74-1.93 (m, 2H), 1.52-1.67 (m, 1H), 0.93-1.44 (m,3H), 0.61-0.91 (m, 3H), 0.36-0.48 (m, 2H), 0.01-0.10 (m, 2H). 28 CD3OD8.04 (s, 0.7H), 7.92 (s, 0.3H), 7.55-7.73 500.31 (m, 1H), 6.91-7.05 (m,1H), 6.48-6.73 M + H (m, 3H), 2.87-5.06 (m, 12H), 2.24-2.74 (m, 2H),1.91-1.86 (m, 1H), 1.71-1.86 (m, 1H), 1.09-1.67 (m, 8H), 0.77-1.04 (m,2H), 0.42-0.70 (m, 2H), 0.05-0.34 (m, 2H).

TABLE 5 Deuterated solvent used for NMR Example measurement NMR data M/S29 DMSO-d6 9.38 (br s, 1H), 8.91 (br s, 0.3H), 8.74 472.24 (br s, 0.7H),8.25-8.29 (m, 1H), 7.35- M + H 7.51 (m, 3H), 7.02 (d, 0.7H, J = 8.2 Hz),6.95 (d, 0.3H, J = 8.7 Hz), 6.65- 6.70 (m, 1.3H), 6.50-6.57 (m, 0.7H),4.40 (dd, 0.7H, J = 6.0, 2.3 Hz), 3.89- 4.00 (m, 1.7H), 3.00-3.57 (m,9.6H), 2.87-2.92 (m, 1H), 2.47-2.57 (m, 1H), 1.91-2.10 (m, 1H),1.64-1.77 (m, 1H), 1.31-1.59 (m, 3H), 1.10 (br s, 1H), 0.48-0.69 (m,4H), 0.33-0.39 (m, 1H). 30 DMSO-d6 11.82-11.95 (m, 1H), 9.36 (br s, 1H),472.26 9.00 (br s, 0.3H), 8.85 (br s, 0.7H), M + H 7.35-7.47 (m, 2H),6.98 (d, 0.7H, J = 7.3 Hz), 6.93 (d, 0.3H, J = 7.8 Hz), 6.46-6.67 (m,2H), 6.12-6.21 (m, 1H), 4.29-4.37 (m, 0.7H), 3.96-4.04 (m, 1H),3.81-3.87 (m, 3H), 2.84-3.63 (m, 12H), 1.89-2.00 (m, 1H), 1.59-1.71 (m,1H), 1.43-1.54 (m, 1H), 1.27-1.38 (m, 2H), 0.96-1.13 (m, 1H), 0.33-0.62(m, 5H). 31 CD3OD 7.68-7.89 (m, 1H), 7.50-7.66 (m, 1H), 486.21 7.12(d,0.7H, J = 8.7 Hz), 7.06 (d, 0.3H, M + H J = 8.2 Hz), 6.61-6.78 (m, 2H),6.45 (t, 0.7H, J = 6.9 Hz), 6.39 (t, 0.3H, J = 6.9 Hz), 3.62 (s, 2.1H),3.60 (s, 0.9H), 3.09-5.35 (m, 10H), 2.86-3.08 (2H, m), 2.69-2.85 (m,1H), 2.07-2.21 (m, 1H), 1.46-1.96 (m, 4.7H), 1.08-1.21 (m, 1.3H),0.68-0.96 (m, 3H), 0.43-0.57 (m, 2H). 32 CD3OD 7.45-7.66 (m, 1H), 7.11(d, 0.7H, J = 486.22 8.2 Hz), 7.06 (d, 0.3H, J = 8.7 Hz), M + H6.61-6.79 (m, 2H), 6.27 (d, 0.7H, J = 6.9 Hz), 6.21 (d, 0.3H, J = 7.3Hz), 3.11-5.00 (m, 10H), 3.02 (dd, 1H, J = 13.3, 7.3 Hz), 2.69-2.94 (m,2H), 2.34 (s, 2.1H), 2.30 (s, 0.9H), 2.05-2.20 (m, 1H), 1.46-1.92 (m,4.7H), 1.06-1.21 (m, 1.3H), 0.70-0.95 (m, 3H), 0.42-0.55 (m, 2H). 33CD3OD 8.06 (s, 0.8H), 7.94 (br s, 0.2H), 7.73 486.21 (d, 0.8H, J = 8.7Hz), 7.56-7.66 (m, M + H 0.2H), 7.02-7.17 (m, 1H), 6.48-6.82 (m, 3H),3.09-4.98 (m, 13H), 3.03 (dd, 1H, J = 13.3, 7.3 Hz), 2.73-2.96 (m, 2H),2.07-2.22 (m, 1H), 1.39-1.96 (m, 4.8H), 0.90-1.34 (m, 2.2H), 0.70-0.88(m, 2H), 0.42-0.58 (m, 2H). 34 CD3OD 7.58 (dd, 0.7H, J = 9.2, 6.9 Hz),7.46- 486.22 7.54 (m, 0.3H), 7.13 (d, 0.7H, J = 8.2 M + H Hz), 7.07 (d,0.3H, J = 8.7 Hz), 6.55- 6.84 (m, 3H), 6.38-6.51 (m, 1H), 3.26- 5.26 (m,13H), 2.89-3.11 (m, 2H), 2.70- 2.86 (m, 1H), 2.07-2.22 (m, 1H), 1.83-2.01 (m, 1H), 1.33-1.77 (m, 4H), 1.09- 1.21 (m, 1H), 0.71-1.04 (m, 3H),0.43- 0.57 (m, 2H).

Reference Example 7-1 Synthesis of 2,2,2-trichloroethyl(1S,3aR,6aS,6R,11bR,11cS)-10-hydroxy-1,2,3a,4,5,6,7,11c-octahydro-3H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carboxylate

To a 100-mL recovery flask, 2,2,2-trichloroethyl(1S,3aR,5aS,6R,11bR,11cS)-10-methoxy-1,2,3a,4,5,6,7,11c-octahydro-3H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carboxylate(972.7 mg, 2.00 mmol) synthesized according to the method described inWO2014/136305, Example 34, (1) was added, and dissolved in methylenechloride (20 mL). The reaction solution was cooled to 0° C., then a 1 Msolution of boron tribromide in methylene chloride (6 mL) was added tothe reaction solution with vigorous stirring, and then the resultingmixture was stirred for 1 hour with warming to room temperature.

To the reaction solution, saturated aqueous sodium hydrogen carbonate(30 mL) was added, and then the resulting mixture was extracted withchloroform (20 mL×3). The combined organic layers were dried overanhydrous sodium sulfate, then the insoluble substance was separated byfiltration, and the filtrate was concentrated under reduced pressure toobtain the title compound (1.04 g, >100%) as white foam-like substance.The crude product was used as it was for the following reaction withoutany further purification.

Reference Example 7-2 Synthesis of 2,2,2-trichloroethyl(1S,3aR,5aS,6R,11bR,11cS)-10-hydroxy-14-(2,2,2-trifluoroacetyl)-1,2,3a,4,5,6,7,11c-octahydro-3H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carboxylate

To a 100-mL recovery flask, 2,2,2-trichloroethyl(1S,3aR,5aS,6R,11bR,11cS)-10-hydroxy-1,2,3a,4,5,6,7,11c-octahydro-3H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carboxylate(1.04 g) synthesized in Reference Example 7-1 was added, and dissolvedin THF (20 mL). To the obtained solution, triethylamine (2.79 ml, 20mmol) and trifluoroacetic anhydride (1.41 mL, 10 mmol) were added, andthe resulting mixture was stirred at room temperature for 1 hour. Thereaction solution was concentrated under reduced pressure. The residuewas diluted with saturated aqueous sodium hydrogen carbonate (50 mL),and then extracted with ethyl acetate (30 mL×2). The combined organiclayer was dried over anhydrous sodium sulfate, then the insolublesubstance was separated by filtration, and the filtrate was concentratedunder reduced pressure to obtain the title compound (1.46 g, >100%) aswhite foam-like substance. The crude product was used as it was for thefollowing reaction without any further purification.

Reference Example 7-3 Synthesis of2,2,2-trifluoro-1-((1S,3aR,5aS,6R,11bR,11cS)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-14-yl)ethan-1-one

To a 100-mL recovery flask, 2,2,2-trichloroethyl(1S,3aR,6aS,6R,11bR,11cS)-10-hydroxy-14-(2,2,2-trifluoroacetyl)-1,2,3a,4,5,6,7,11c-octahydro-3H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carboxylate(1.46 g) synthesized in Reference Example 7-2 was added, and dissolvedin acetic acid (25 ml. To the obtained solution, zinc powder (1.31 g, 20mmol) was added, and the resulting mixture was stirred at roomtemperature for 2 hours. The reaction solution was filtered throughCelite to remove excessive zinc powder. The filtrate was concentratedunder reduced pressure, and then azeotroped with toluene. The residuewas diluted with saturated aqueous sodium hydrogen carbonate (80 mL),and then extracted with chloroform (30 mL×3). The combined organiclayers were dried over anhydrous sodium sulfate, then the insolublesubstance was separated by filtration, and the filtrate was concentratedunder reduced pressure. The obtained residue was subjected to columnchromatography (aminosilica gel, 16 g) using ethyl acetate and methanol(concentration gradient, 0 to 30%) as the elution solvent to obtain thetitle compound (215 mg, total yield of 27% for 3 steps) as pale yellowfoam-like substance.

¹H NMR CDCl₃: 6.96-7.06 (m, 1H), 6.64-6.72 (m, 1H), 6.52-6.58 (m, 1H),5.90 (br s,1H), 4.90 (d, 0.5H, J=6.8 Hz), 4.34 (dd, 0.5H, J=6.6, 13.8Hz), 4.18-4.24 (m, 0.6H, 2.72-3.81 (m, 8.5H, 2.21-2.46 (m, 1H, 1.46-2.00(m, 3H), 0.99-1.43 (m, 4H)

Reference Example 8-1 Synthesis of ethyl3-oxo-2,3-dihydro-1H-pyrazole-4-carboxylate

This compound was synthesized according to the method described inWO2011/090935.

To a 500-mL recovery flask, a 20% solution of sodium ethoxide in ethanol(60 ml) and ethyl 2-(ethoxymethylene)malonate (10.5 mL, 524 mmol) wereadded, and the resulting mixture was stirred at room temperature for 10minutes. To the obtained mixture, hydrazine monohydrate (5.1 mL, 104mmol) was added, the resulting mixture was stirred at 80° C. for 18hours with heating, and then the obtained yellow suspension was cooledto 0° C. 7 the reaction solution vigorously stirred, 1 N hydrochloricacid (180 mL) was slowly added to the mixture at the same temperature toobtain a yellow solution. To the obtained solution, ethyl acetate (150mL) was added, and the resulting mixture was stirred at room temperaturefor 1 hour. The organic layer was separated, and then the aqueous layerwas extracted with ethyl acetate (100 mL×2). The combined organic layerswere dried over anhydrous sodium sulfate, and the insoluble substancewas separated by filtration. The filtrate was concentrated under reducedpressure, and the obtained residue was crystallized by using ethylacetate and hexane to obtain the title compound (2.82 g, 35%) as yellowcrystals (mixture of tautomers). MS ES M−H=155

Reference Example 8-2 Synthesis of3-methoxy-1-methyl-1H-pyrazole-4-carboxylic acid

To a 50-mL round bottom flask, ethyl3-oxo-2,3-dihydro-1H-pyrazole-4-carboxylate (200 mg, 1.28 mmol),iodomethane (397 μL, 6.40 mmol), and DMF (5 mL) were added, sodiumhydride (60%, dispersed in liquid paraffin, 256 mg, 6.40 mmol) was addedto the mixture, and the resulting mixture was stirred at roomtemperature for 22 hours. Under ice cooling, water was added to thereaction solution, and the resulting mixture was extracted three timeswith ethyl acetate. The combined organic layers were dried overanhydrous sodium sulfate, then the insoluble substance was separated byfiltration, and the filtrate was concentrated under reduced pressure.The residue was subjected to silica gel column chromatography (25 g)using ethyl acetate and hexane (concentration gradient, 5 to 60%) as theelution solvent to obtain ethyl3-methoxy-1-methyl-1H-pyrazole-4-carboxylate (51 mg, 22%) as whitesolid.

To a 50-mL round bottom flask, ethyl3-methoxy-1-methyl-1H-pyrazole-4-carboxylate (51 mg, 0.279 mmol)obtained above was added, and dissolved in ethanol (1 mL), then 5 Naqueous sodium hydroxide (0.5 mL, 2.50 mmol) was added to the solution,and the resulting mixture was stirred at room temperature for 3 days. Tbthe reaction solution, a 1 N hydrochloric acid (2.7 mL) was added, andthe resulting mixture was concentrated under reduced pressure. Theobtained residue was dissolved in THF, the insoluble substance wasseparated by filtration using Celite, and the filtrate was concentratedunder reduced pressure to obtain the title compound (43 mg, 100%) aswhite powder.

¹H NMR DMS-d₆: 11.91 (br s, 1H, 7.99 (s, 1H), 3.80 (s, 3H), 3.69 (s, 3H)

Example 35 Synthesis of6-((1S,3aR,5aS,8R,11bR,11c)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one

To a 10m-L test tube,2,2,2-trifluoro-1-((1S,3aR,5aS,6R,11bR,11cS)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-14-yl)ethan-1-one(64 mg, 136 μmol) synthesized in Reference Example7-3,6-oxo-1,6-dihydropyridine-2-carboxylic acid (67 mg, 0.48 mmol, andHATU (197 mg, 0.52 mmol) were added, and suspended in THF (2 mL), thentriethylamine (100 μL, 0.72 mmol) and DMA (100 μL) were added to thesuspension, and the resulting mixture was stirred at room temperaturefor 1.6 hours.

To the reaction mixture, ethanolamine (100 μL) and methanol (2 mu wereadded, and the resulting mixture was stirred at the same temperature for1 hour. The reaction solution was concentrated under reduced pressure,the obtained residue was dissolved in chloroform (30 mL), and thesolution was washed with 6% aqueous ammonia (10 mL×3). The combinedaqueous layers were extracted with chloroform (20 mL). The combinedorganic layers were dried over anhydrous magnesium sulfate, theinsoluble substance was separated by filtration, and then the filtratewas concentrated under reduced pressure. The obtained residue wassubjected to column chromatography (aminosilica gel, 16 g) usingmethanol and chloroform (concentration gradient, 10 to 30%) as theelution solvent to obtain6-((1S,3aR,5aS,6R,11bR,11cS)-10-hydroxy-14-(2,2,2-trifluoroacetyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-ono(M+H=514.26) as white foam-like substance.

6-((1S,3aR,5aS,6R,11bR,11cS)-10-Hydroxy-14-(2,2,2-trifluoroacetyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-oneobtained above was dissolved in methanol (5 mL) in a 100-mL recoveryflask, sodium borohydride (124 mg, 3.26 mmol) was added to the solution,and the resulting mixture was stirred at room temperature for 2 hours.The reaction solution was concentrated under reduced pressure, theresidue was suspended in 6% aqueous ammonia (20 mL), and the suspensionwas washed with chloroform (20 mL×2). The aqueous layer was concentratedunder reduced pressure, and the residue was subjected to columnchromatography (aminosilica gel, 12 g) using methanol and chloroform(concentration gradient, 10 to 30%) as the elution solvent, and therebypurified to obtain a mixture of6-((1S,3aR5aS,6R,11bR,11cS)-10-hydroxy-14-(2,2,2-trifluoroacetyl-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one,and the title compound,6-((1S,3aR,5aS,6R,11bR,11cS)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one.

The mixture obtained above was dissolved in concentrated aqueous ammonia(3 mL) in a 50-mL recovery flask, and the solution was heated at 80° C.for 18 hours in a tube sealed with a rubber stopper. The reactionmixture was concentrated under reduced pressure, and the residue wassubjected to column chromatography (aminosilica gel, 7 g) using methanoland chloroform (concentration gradient, 10 to 50%) as the elutionsolvent. The obtained crude product was powdered by using methanol (0.2mW and t-butyl methyl ether (3 mV to obtain the title compound (23 mg,41%).

¹H NMR DMSO-d₆: 9.08 (s, 1H), 7.53 (dd, 0.7H, J=6.9, 8.7 Hz), 7.47 (dd,0.3H, J=7.3, 9.2 Hz), 6.92 (d, 0.7H, J=8.2 Hz), 6.87 (d, 0.3H, J=7.8Hz), 6.39-6.58 (m, 4H), 4.42-4.45 (m, 0.7H), 4.13-4.17 (m, 0.3H),3.89-3.94 (m, 0.3H), 3.71-3.76 (m, 0.7H), 3.61 (d, 0.7H, J=11.0H),3.45-3.48 (m, 0.3H), 3.15-3.27 (m, 1H), 2.80-3.09 (m, 5H), 2.64-2.73 (m,1H), 2.13-2.44 (m, 2H), 1.63-1.70 (m, 1H), 1.25-1.59 (m, 2H), 1.12-1.15(d, 1H, J=11.0 HZ), 1.01-1.07 (m, 1H), 0.88-0.94 (m, 1H), 0.66-0.74 (m,1H)

Example 36 Synthesis of4-((1S,3aR,5aS,6R,1bR,11S)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methyl-1,2-dihydro-3H-pyrazol-3-one

(1S,3aR,5aS,6R,11bR,11cS)-14-(Cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol(30 mg, 86 μmol), 3-methoxy-1-methyl-1H-pyrazole-4-carboxylic acid (29mg, 0.19 mmol), diisopropylethylamine (75 μL, 0.43 mmol), and HATU (72mg, 0.19 mmol) were reacted in the same manner as that of Example 1,except that THF (2 mV alone was used as the solvent. To the reactionsolution, a 1.4 N solution of ammonia in methanol was added to terminatethe reaction, and then the reaction solution was concentrated underreduced pressure. The residue was suspended in saturated aqueous sodiumhydrogen carbonate, and then the suspension was extracted withchloroform. The organic layer was dried over anhydrous sodium sulfate,the insoluble substance was separated by filtration, and then thefiltrate was concentrated under reduced pressure. The obtained residuewas subjected to column chromatography (silica gel, 10 g) using methanoland ethyl acetate (concentration gradient, 0 to 30%) as the elutionsolvent, and thereby purified to obtain((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-1,2,3a,4,5,6,7,11c-octahydro-3H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-3-yl)(3-methoxy-1-methyl-1H-pyrazol-4-yl)methanone(83.3 mg, 80%) as pale yellow amorphous substance.

¹H NMR CD₃OD: 7.69 (s, 0.7H), 7.55 (s, 0.3H), 6.90-6.96 (m, 1H), 6.63(d, 0.7H, J=2.8 Hz), 6.53-6.68 (m, 1.3H), 2.78-5.02 (m, 8H), 3.90 (s,3H, 3.73 (s, 2.1H), 3.68 (s, 0.9H), 2.53-2.57 (m, 1H), 2.31-2.33 (m,2H), 1.90-2.09 (m, 2H), 1.66-1.76 (m, 1H), 1.51-0.78 (m, 7H) 0.46-0.48(m, 2H), 0.09-0.12 (m, 2H) To a 30-mL round bottom flask,((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-1,2,3a,4,5,6,7,11c-octahydro-3H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-3-yl)(3-methoxy-1-methyl-1H-pyrazol-4-yl)methanone(15 mg, 31 μmol) obtained above was added, and dissolved in methylenechloride (1 mL). A 1.0 M solution of boron tribromide in methylenechloride (153 μL, 0.15 mmol) was added to the solution under icecooling, and the resulting mixture was stirred at room temperature for 1hour. A 1.4 N solution of ammonia in methanol was added to terminate thereaction, and then the reaction solution was concentrated under reducedpressure. The residue was suspended in saturated aqueous sodium hydrogencarbonate, and then the suspension was extracted with chloroform. Theorganic layer was dried over anhydrous sodium sulfate, the insolublesubstance was separated by filtration, and then the filtrate wasconcentrated under reduced pressure. The obtained residue was subjectedto preparative TLC using methanol containing aqueous ammonia andchloroform (concentration, 10%) as the developing solvent to obtain thetitle compound (10.6 mg, 73%) as pale yellow amorphous substance.¹H NMR DMSO-d₆: 11.47 (s, 0.1H), 11.37 (s, 0.9H), 9.11 (s, 1H), 8.09 (s,0.9H), 7.48 (s, 0.1H), 6.94 (d, 1H, J=8.2H), 6.60 (d, 1H, J=2.3 Hz),6.64 (dd, 11H, J=8.2,2,3H), 4.33-4.50 (m, 1H), 2.50-4.07 (m, 12H),2.19-2.34 (m, 2H), 1.80-2.00 (m, 2H), 1.58-1.85 (m, 1H), 0.70-1.43 (m,6H), 0.38-0.53 (m, 2H), 0.02-0.16 (m, 2H)

Example 37 Synthesis of5-chloro-3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one

(1S,3aR,5aS,6R,11bR,11cS)-14-(Cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol(20 mg, 57 μmol), 6-chloro-2-oxo-1,2-dihydropyridine-9-carboxylic acid(22 mg, 0.13 mmol), diisopropylethylamine (50 μL, 0.29 mmol), and HATU(72 mg, 0.13 mmol) were reacted in the same manner as that of Example 1,except that THF (1 mmol) alone was used as the solvent. Tb the reactionsolution, a 1.4 N solution of ammonia in methanol was added to terminatethe reaction, and then the reaction solution was concentrated underreduced pressure. The residue was suspended in saturated aqueous sodiumhydrogen carbonate, and then the suspension was extracted withchloroform. The organic layer was dried over anhydrous sodium sulfate,the insoluble substance was separated by filtration, and then thefiltrate was concentrated under reduced pressure. The obtained residuewas subjected to column chromatography (aminosilica gel, 8 g) usingmethanol and ethyl acetate (concentration gradient, 0 to 80%) as theelution solvent, and thereby purified to obtain the title compound (11.6mg, 40%) as brown amorphous substance.

¹H NMR DMSO-d₆: 11.99 (br s, 1H), 9.06 (br s, 1H), 7.68 (s, 0.7H), 7.59(s, 0.3H), 7.48 (d, 1H, J=2.3 Hz), 6.89 (d, 0.7H, J=8.2 Hz), 6.85 (d,0.3H, J=8.2 Hz), 6.40-6.56 (m, 2H), 4.25-4.32 (m, 0.7H), 8.93-3.98 (m,0.3H), 3.78-3.84 (m, 0.3H), 2.11-3.62 (m, 10.7H), 1.68-1.91 (m, 21),1.48-1.63 (m, 1H), 0.87-1.46 (m, 4H), 0.50-0.79 (m, 2H), 0.29-0.47 (m,2H), 0.06-0.12 (m, 2H)

Example 38 Synthesis of5-((1S,3aR,5aS,6R,11bR,11c)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methenonaphtho[1,2-e]indole-3-carbonyl-1,3-dimethylpyrimidine-2,4(1H,3H)-dione

In the same manner as that of Example 1,(1S,3aR,5aS,6R,11bR,1cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol(35 mg, 98 μmol),1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid(35 mg, 0.19 mmol), triethylamine (70 μL, 0.50 mmol, and HATU (145 mg,0.38 mmol) were reacted, then to the reaction solution, a 2 N solutionof ammonia in methanol was added to terminate the reaction, and then thereaction solution was concentrated under reduced pressure. The residuewas suspended in 6% aqueous ammonia (20 mL), and the suspension wasextracted with ethyl acetate (15 mL×2). The combined organic layers werewashed with saturated brine (10 mL), and then dried over anhydrousmagnesium sulfate. The insoluble substance was separated by filtration,and then the filtrate was concentrated under reduced pressure. Theresidue was subjected to column chromatography (aminosilica gel, 10 g)using methanol and ethyl acetate (concentration gradient, 0 to 30%) asthe elution solvent, and thereby purified. The obtained syrup-likesubstance was dissolved in methanol (0.2 mL), then powdered by addingt-butyl methyl ether (3 mL) to the solution, and collected by filtrationto obtain the title compound (39 mg, 76%) as white powder.

¹H NMR CD₃OD: 7.82 (s, 1H), 6.92-6.98 (m, 1H), 6.52-6.65 (m, 2H),4.53-4.62 (m, 1H), 4.02-4.18 (m, 1), 3.50-3.80 (m, 2H), 3.42 (s, 2H),3.37 (s, 1H), 3.33 (s, 2H), 3.31 (s, 1H), 2.81-3.18 (m, 5H), 2.57-2.59(m, 1H), 2.30-2.38 (m, 2H), 1.93-2.09 (m, 2H), 1.67-1.78 (m, 1H),1.43-1.59 (m, 2H), 1.10-1.29 (m, 2H), 0.81-0.95 (m, 2H), 0.44-0.53 (m,2H), 0.08-0.17 (m, 2H)

Example 39 Synthesis of6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-methoxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one

The experiment was performed in the same manner as that of Example 1.

(1S,3aR,6aS,6R,11bR,11cS)-14-(Cyclopropylmethyl)-10-methoxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole(82 mg, 0.23 mmol) prepared according to the method described inWO2013/036833, Example 67, triethylamine (200 μL, 1.43 mmol), and HATU(167 mg, 0.44 mmol) were reacted. Then, to the reaction solution,ethanolamine (200 μL) and methanol (1 mL) were added to terminate thereaction, and then the reaction mixture was diluted with ethyl acetate(50 mL), and washed with 6% aqueous ammonia (50 mL). The aqueous layerwas extracted with chloroform (30 mL×2), and the combined organic layerswere dried over anhydrous sodium sulfate. The insoluble substance wasseparated by filtration, and then the filtrate was concentrated underreduced pressure. The residue was subjected to column chromatography(aminosilica gel, 7 g) using methanol and ethyl acetate (concentrationgradient, 10 to 50%) as the elution solvent, and thereby purified. Theobtained syrup-like substance was dissolved in methanol (0.2 mL), andthen powdered by adding t-butyl methyl ether (3 mL) to the solution. Theobtained powder was dried at 100° C. for 16 hours under reduced pressureto obtain the title compound (87 mg, 100%) as white amorphoussubstance-like substance.

¹H NMR DMSO-d₆: 7.5 (br s, 1H), 6.97-7.03 (m, 1H), 6.45-6.73 (m, 4H),4.40-4.45 (m, 0.7H), 3.84-3.89 (m, 0.3H), 3.69 (s, 3H), 3.66-3.62 (m,1H), 2.95-3.22 (m, 4H), 2.79-2.84 (m, 2H), 2.13-2.62 (m, 4H), 1.79-1.87(m, 2H), 1.26-1.60 (m, 3H), 0.99-1.14 (m, 3H), 0.70-0.74 (m, 1H),0.54-0.61 (m, 1H), 0.39-0.40 (m, 2H), 0.00-0.07 (m, 2H)

Example 40

The functional activities of the compounds provided by the presentinvention on the μ, δ, and κ opioid receptors were investigated.

Method:

The test was performed by using Lance Ultra cAMP Kit (PerkinElmer)according to a method predetermined for the kit. In the evaluation ofthe agonistic activity, CHO cells expressing each of the human opioidreceptors (δ, μ, and κ, accession numbers and catalog numbers arementioned below) and 10 μM of each test compound were reacted for 30minutes in an assay buffer (1× HBSS, 1 M HEPES, pH 7.4, 250 mM IBMX(isobutylmethylxanthine), 7.5% BSA) in the presence of forskolin.Subsequently, the cAMP detection reagent included in the kit was added,and 1 hour afterward, time-resolved fluorescence measurement wasperformed by using the EnVision plate reader (PerkinElmer). The testcompounds and the control drugs (δ: SNC80, μ: DAMGO, κ: U-69593) wereevaluated in a concentration range of 1012 to 10⁻⁵ M, a dose-responsecurve of each test compound was obtained from the fluorescence values at665 nm, and EC₅₀ value and the E_(max), value were calculated. TheE_(max) value was calculated as a ratio of the maximum reaction of thetest compound to the maximum reaction of each control drug, which istaken as 100%.

SNC80:(+)-4-[(αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybensyl]-N,N-diethylbenzamideDAMGO: [D-Ala²,N-MePhe⁴,Gly-ol]enkephalin U-69693:(+)-(5α,7α,8β)-N-Methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]benzeneacetamideAccession Numbers and Catalogue Numbers

δ: Catalog No. CT4607, Accession No. NM_000911.2μ: Catalog No. CT4606, Acceasion No. NM_000914κ: Catalog No. CT4606, Accession No. NM_000912

(ChanTost Corporation)

TABLE 6 δ receptor μ receptor κ receptor Ex- EC₅₀ EC₅₀ EC₅₀ am- valueEmax value Emax value Emax ple (nM) (%) (nM) (%) (nM) (%) 1 <3 88 N.C.8.3* >1 12 3 <3 98 >1 20 <1 15 4 <3 86 N.C. 5.5* >10 27 5 <3 81 >1 9.7<1 20 6 <3 97 >10 7.7 N.C. 3.2* 7 <3 99 >1 10 N.C. −0.9* 8 <3 70 >1 8.6<1 21 9 <3 74 <1 16 <1 14 10 <3 74 N.C. 6.0* N.C. −0.7* 11 <3 76 >1 11N.C. −2.5* 14 <3 95 >1 8.1 N.C. 6.7* 16 <3 92 >1 19 <1 29 19 <3 91 >1 19N.C. 0.6* 28 <3 92 >1 16 <1 13 31 <3 97 >10 7.7 N.C. 3.2* 32 <3 70 >18.6 <1 21 N.C.: Since the maximum reaction was not reached at themaximum concentration (10 μM), the ED₅₀ value was not calculated. *Sincethe maximum reaction was not reached at the maximum concentration, areaction rate at the maximum concentration is mentioned as a referencevalue.

As shown in Table 6, it was confirmed that the compounds of the presentinvention have potent agonistic activities for the opioid δ receptor,but do not have agonistic activity or have only very weak agonisticactivity for the μ and κ receptors.

Example 41 Mouse Elevated Plus Maze Test (Test Method)

For the test, 5 to 6 weeks old C57BL/6N male mice were used. On a plusmaze apparatus consisting of a wall-less running route (open arm, width6 cm, length 30 cm) and a running route with a wall (closed arm, width 6cm, length 30 cm, height of wall 15 cm), and having a height of 40 cm, amouse was put so as to be directed to the running route with a wall, andallowed to spontaneously enter into the plus maze. Each test substancewas dissolved in saline or 0.005 N HCl in saline, and subcutaneouslyadministered on the back 30 minutes before the start of the test. At thetime of the start of the test, video recording with a video camera wasstarted, the time at which the mouse entered into the plus maze isconsidered to be the start of the test, and exploratory behavior wasrecorded for 5 minutes. On the basis of the video image, staying time inthe running routes were determined, and wall-less running route stayingtime ratio (%) was calculated.

(Test Results)

As shown in FIGS. 1 and 2 , from this experiment, it was found thatsubcutaneous administrations of the compound 1 (the compound describedin Example 1) and the compound 7 (the compound described in Example 7)at a dose of 3 mg/kg and 1.0 mg/kg, respectively, significantlyincreased the wall-less running route staying time ratio and thus it wasconfirmed that they exhibit anxiolytic-like effects. The compound 3 (thecompound described in Example 3), the compound 9 (the compound describedin Example 9), and the compound 10 (the compound described in Example10) also showed a tendency of increasing the wall-less running routestaying time ratio (FIGS. 3 to 5 ).

Example 42 Rat Elevated Plus Maze Teat

Anxiolytic effects of the compounds provided by the present inventionwere investigated by the rat elevated plus maze test.

(Test Method)

For the test, 7 to 9 weeks old Wistar male rats were used. On a plusmaze apparatus consisting of a wall-less running route (width 10 cm,length 50 cm) and a running route with a wall (width 10 cm, length 50cm, height of wall 30 cm), and having a height of 50 cm, a rat was putso as to be directed to the running route with a wall, and allowed tospontaneously enter into the plus maze, and exploratory behavior wasobserved for 5 minutes. Each test substance was dissolved in a 4.5%aqueous solution of cyclodextrin, and orally administered 2 hours beforethe start of the test. The test data were automatically analyzed byusing video image action analysis software (Smart3.0, PanLab S.L.,PanLab), and wall-less running route staying time ratio (%) wascalculated.

(Test Results)

As shown in FIG. 6 , from this experiment, it was found that oraladministration of 3 mg/kg of each of the compound 7 (the compounddescribed in Example 7), the compound 3 (the compound described inExample 3), and the compound 10 (the compound described in Example 10)significantly increased the wall-less running route staying time ratio,and thus it was confirmed that they exhibit anxiolytic-like effects.

Example 43

herG (Human Ether-s-a-go-go-Related Gene) Potassium Channel InhibitionTest

(Test Method)

The test was performed with Port-a-Patch automatic patch clump apparatus(Nanion Technologies) using hERG channel-stably expressing CHO cells(purchased from Channelopathy Foundation). The membrane potential of thecells was maintained at −80 mV, then there were applied a depolarisationpulse at +20 mV for 1.5 seconds, and a following test pulse at −60 mVfor 1.6 seconds at a frequency of 1 time per 10 seconds, and the hERGcurrent was confirmed as a tail current induced by the test pulse. Thetest compound was dissolved in an extracellular fluid (137 mM NaCl, 4 mMKCl, 1.8 mM CaCl₂, 1 mM MgCl₂, 10 mM D(+)-glucose, 10 mM HEPES, pH 7.4),and the solution was refluxed at room temperature for 5 minutes. Theinhibition ratio was obtained from the ratio of the tail current valueobserved after the compound was applied based on the tail current valueobserved before the compound was applied, which was taken as 100%. Forthe test, we used cells that showed a peak tail current value notsmaller than 300 pA, tail current run-down smaller than 10% of theinitial current value, and leak current smaller than 200 pA.

(Test Results)

The test results are shown in Table 7.

In the table, the compounds 1, 3, 7, 9, and 10 are the compoundsdescribed in Examples 1, 3, 7, 9, and 10, respectively.

As clearly seen from the results shown in Table 7, all the testcompounds showed only weak inhibitory effects.

On the other hand, it was revealed that the compounds disclosed inWO2013/35833 (Patent document 4) include those having potent hERGinhibitory effects.

TABLE 7 hERG channel inhibitory Example Concentration action Compound 110 μM <50% Compound 3 10 μM <50% Compound 7 10 μM <50% Compound 9 10 μM<50% Compound 10 10 μM <50% Comparative 10 μM >50% compound 1Comparative 10 μM >50% compound 2Comparative compound 1: Compound of WO2013/35833, Example 93 (compound104)Comparative compound 2: Compound of WO2013/35833, Example 205 (compound267)

Example 4 Hyperemotional Reaction Inhibition Test Using OlfactoryBulbectomized (OBX) Rat (Test Method)

According to the method of Saitoh et al. (Saitoh A, Yamada M, Yamada M,Takahashi K, Yamaguchi K, Murasawa H, Nakatani A. Tatsumi Y. Hirose N,and Kamei J: Antidepressant-like effects of the delta-opioid receptoragonist SNC80((+)-4-[(alphaR)-alpha-[(2S,5R)-2,5-dimethyl-4-(2-propenyl)-1-piperazinyl]-(3-methoxyphenyl)methyl]-N,N-diethylbenzamide)in an olfactory bulbectomized rat model, Brain Res., 2008,1208:160-169), OBX rate were prepared by extracting the rat olfactorybulbs, and then breeding the rate in an isolated circumstance.Hyperemotional reaction was evaluated on the day 14 after the surgicaloperation and before the division into groups, and 2 hours after theadministration on the days 1, 4, 7, 10, and 14 of the administrationperiod according to the hyperemotional reaction evaluation criteriaprepared by Gomita et al. (Gomita et al., Behavioral pharmacological andelectroencephalographical studies of7-chloro-1-methyl-5-phenyl-1H-1,6-benzodiazepine-2,4-(3H,5H)-dione(Clobazam), Folia Pharmacologica Japonica, 82, 267 (1983)). The drug wassubcutaneously administered once a day continuously over 14 days. As apositive control drug, fluoxetine, which is a selective serotoninreuptake inhibitor (SSRI), was used. As the solvent, a 1% cyclodextrin(CD) was used.

(Test Results)

Administration of 0.1 mg/kg of the test substance (the compounddescribed in Example 7 mentioned above) significantly reduced thehyperemotional reactions of the OBX rats from the day 4 of theadministration period compared with the solvent administration group,and restored the condition even to a level comparable to that of therats of the sham surgery group on the day 7 of the administrationperiod. Administration of 1 mg/kg of the test substance significantlyreduced the hyperemotional reactions of the OBX rats from the day 1 ofthe administration period compared with the solvent administrationgroup, and restored the condition even to a level comparable to that ofthe rate of the sham surgery group on the day 4 of the administrationperiod. These effects were maintained until the day 14. On the otherhand, administration of fluoxetine at 10 mg/kg significantly reduced thehyperemotional reactions of the OBX rats on the day 14 of theadministration period compared with the solvent administration group.

From the above investigation, it was suggested that the test substancemay possibly show antidepressant-like effects even with singleadministration, unlike SSRI. It was also suggested that tolerance maynot be induced for the antidepressant-like action of the test substance.

Example 45 Reserpine-Induced Parkinson's Disease Model Mouse (TestMethod)

ICR male mice (6 weeks old, Japan SLC) were obtained, and used after anacclimation period (5 to 12 days).

PD model was prepared with reference to the report of Hille et al. (Exp.Neurol., 2001, 172:189). It was prepared by intraperitoneallyadministering reserpine (6 mg/kg) 18 to 24 hours before the start of thetest. The test was performed by subcutaneously administering a testcompound to each mouse on the day of the test, immediately putting themouse into a cage for monitoring locomotor activity, and measuring themigration distance over 60 minutes.

(Test Results)

Since administration of the test substance (the compound described inExample 7 mentioned above) at 10 mg/kg significantly increasedexploratory behavior, and also, a tendency of increase of standing upbehavior was found, although it was not significant (P=0.16),Parkinson's disease-curing effect of the test substance was suggested.

Example 46 Evaluation Using Rat Cerebral Infarction-Induced OveractiveBladder Model (Test Method)

A transient middle cerebral artery occlusion model was prepared by using8 weeks old SD male rats under isoflurane inhalation anesthesia. On thenext day, the cervix was slightly cut open again under the isofluraneinhalation anesthesia, and a catheter for administration was fixed inthe jugular vein, and led to the back. A cytometry operation was alsoperformed, and the other end of a cannula inserted into the bladder wasled to the back, and connected to a cannula swivel.

On the day 4 after the cerebral ischemia operation, cytometry wasperformed under no anesthesia and with no restraint. Intravesicalpressure was measured for the stable period, then a medium wasintravenously administered, and the value of the pressure was measuredover about 30 minutes as a value before test substance administration.Then, the test substance was cumulatively and intravenously administeredfrom the lowest dose at intervals of about 80 minutes, and the value wasmeasured for about 30 minutes after each administration. For the ratsdetermined to show pollakiuria (urination interval was 10 minutes orshorter) in the measurement before the administration, staticintravesical pressure, pressure at the time of urination, urinationinterval, and single urination amount were measured at each time point.

(Test Results)

The measurement results are shown in Table 8.

As clearly seen from the results shown in Table 8, the test substance(the compound described in Example 7 mentioned above) did not affect thestatic intravesical pressure and pressure at the time of urination atall the doses. On the other hand, the urination interval and singleurination amount showed a dose-dependently increasing tendency, andtherefore pollakiuria-improving action of the test substance wassuggested.

TABLE 8 n Vehicle 0.01 mg/kg 0.1 mg/kg Static pressure 5 10.6 ± 1.3  9.5± 1.3 9.6 ± 1.1 (mmHg) Pressure at the 5 41.4 ± 10.0 42.9 ± 10.7 42.8 ±9.7  time of urination (mmHg) Urination interval 5 384.4 ± 63.2  450.7 ±76.9  547.4 ± 122.5 (sec) Single urination 5 0.288 ± 0.061 0.310 ± 0.0680.403 ± 0.129 amount (g)Mean±S.E. (n=5)

Example 47 Metabolic Stability Test (Test Method)

Human hepatic microsomes and a test substance were reacted for a certainperiod of time (0 to 60 minutes). The test substance, which was notmetabolized in the reaction sample, was measured, and remaining ratiowas calculated. The test substance-remaining ratio at the time when thereaction time is 0 hour is taken as 100%. The remaining ratio afterincubation was plotted against time as a log-linear plot to obtain aregression line (y=100e^(−kt), k=inclination of straight line: clearancerate constant), and metabolic clearance CL_(int) (mL/min/kg) wascalculated by using the following equation.

CL _(int) *=k(−min)×52.5 (mg MS protein/g liver)×26 (g liver/kg)/MSprotein (mg MS protein/mL)

*: Davies, B. and Morris T., Physiological parameters in laboratoryanimals and humans, Pharm. Res., 10(7):1093-1095, 1993

(Test Results)

The test results are shown in Table 9.

TABLE 9 Example Example Example Example Comparative 1 7 10 16 compound 1Clint 19 5.6 13 18 25Comparative compound 1: WO2013/35833, Example 93 (compound 104)

As clearly seen from the results shown in Table 9, it was revealed thatthe compounds of the present invention have superior metabolicstability. On the other hand, it was revealed that the compoundsdescribed in WO2013135833 (Patent document 4) include those showing badmetabolic stability.

DESCRIPTION OF NOTATIONS

In FIGS. 1 to 6 , the vertical axes indicate the wall-less running routestaying time ratio, and the horizontal axes indicate the test drug anddose thereof.

1. A compound selected from the group consisting of:2-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine1-oxide,4-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine1-oxide,3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,1b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one,3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine1-oxide,5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one,3-((1S,3aR,5aS,6R,11bR,11CS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one,6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one,3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-6-methylpyridin-2(1H)-one,5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one,6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one,4-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one,5-((1S,3aR,5aS,6R,11bR,11cS)-14-cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyrimidine-2,4(1H,3H)-dione,3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-4(1H)-one,2-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-8,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-4(1H)-one,4-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one,6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-8,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridazin-3(2H)-one,4-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)quinolin-2(1H)-one,5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-8,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-2H-pyran-2-one,2-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-4H-pyran-4-one,2-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-4(1H)-one,5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyrazin-2(1H)-one,2-((1S,3aR,5aS,6R,11bR,11cS)-1-acetoxy-14-cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine1-oxide,6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one,3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyrazin-2(1H)-one,6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyrimidine-2,4(1H,3H)-dione,6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-8,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-ethylpyridin-2(1H)-one,6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyrimidin-4(3H)-one,5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-8,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-ethylpyridin-2(1H)-one,6-((1S,3aR,5aS,6R,11bR,11cS)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one,4-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methyl-1,2-dihydro-3H-pyrazol-3-one,5-chloro-3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one,5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1,3-dimethylpyrimidine-2,4(1H,3H)-dione,and6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-methoxy-2,3,3a,4,5,6,7,11c-octahydro-1H-8,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one,or a pharmaceutically acceptable salt the compound.
 2. The compound, ora pharmaceutically acceptable salt the compound according to claim 1,wherein the compound is2-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine1-oxide.
 3. The compound, or a pharmaceutically acceptable salt thecompound according to claim 1, wherein the compound is3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one.4. The compound, or a pharmaceutically acceptable salt the compoundaccording to claim 1, wherein the compound is6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one.5. The compound, or a pharmaceutically acceptable salt the compoundaccording to claim 1, wherein the compound is5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one.6. The compound, or a pharmaceutically acceptable salt the compoundaccording to claim 1, wherein the compound is6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one.7. The compound, or a pharmaceutically acceptable salt the compoundaccording to claim 1, wherein the compound is5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-ethylpyridin-2(1H)-one.8. A medicament comprising the compound, or a pharmaceuticallyacceptable salt the compound according to claim
 1. 9. A pharmaceuticalcomposition comprising the compound, or a pharmaceutically acceptablesalt the compound according to claim 1 as an active ingredient.
 10. Anantidepressant comprising the compound, or a pharmaceutically acceptablesalt the compound according to claim 1 as an active ingredient.
 11. Ananxiolytic drug comprising the compound, or a pharmaceuticallyacceptable salt the compound according to claim 1 as an activeingredient.
 12. A method for ameliorating, preventing or treatingdepression, which comprises administering an effective amount of thecompound, or a pharmaceutically acceptable salt the compound accordingto claim
 1. 13. A method for ameliorating, preventing or treatinganxiety, which comprises administering an effective amount of thecompound, or a pharmaceutically acceptable salt the compound accordingto claim
 1. 14. Use of the compound, or a pharmaceutically acceptablesalt the compound according to claim 1 for ameliorating, preventing ortreating depression.
 15. Use of the compound, or a pharmaceuticallyacceptable salt the compound according to claim 1 for ameliorating,preventing or treating anxiety.
 16. A method for ameliorating,preventing or treating depression in a human, which comprises the stepof administering an effective amount of the compound, or apharmaceutically acceptable salt the compound according to claim 1 tothe human.
 17. A method for ameliorating, preventing or treating anxietyin a human, which comprises the step of administering an effectiveamount of the compound, or a pharmaceutically acceptable salt thecompound according to claim 1 to the human.